CN107073051B - 重组aav变体及其用途 - Google Patents
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- CN107073051B CN107073051B CN201580055773.2A CN201580055773A CN107073051B CN 107073051 B CN107073051 B CN 107073051B CN 201580055773 A CN201580055773 A CN 201580055773A CN 107073051 B CN107073051 B CN 107073051B
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Abstract
在一些方面中,本公开内容涉及具有独特的组织靶向能力的重组腺相关病毒。在一些方面中,本公开内容涉及使用重组腺相关病毒的基因转移方法。在一些方面中,本公开内容涉及分离的AAV衣壳蛋白和编码其的分离的核酸。
Description
相关申请
本申请根据35U.S.C.§119(e)要求于2014年10月21日提交的标题为“RecombinantAAV Variants And Uses Thereof”的美国临时专利申请USSN 62/066,856的权益,其全部内容通过引用并入本文。
技术领域
在一些方面中,本公开内容涉及可用于鉴定细胞中的腺相关病毒(adeno-associated virus)的分离核酸、组合物和试剂盒。在一些方面中,本公开内容提供了新的AAV和其使用方法以及相关试剂盒。
背景技术
腺相关病毒(AAV)是小的辅助病毒依赖性病毒。其在20世纪60年代作为腺病毒(引起感冒的病毒)制备中的污染物被发现。其在细胞中的生长依赖于腺病毒的存在并因此被命名为腺相关病毒。AAV载体已成为用于体内基因转移的有效平台。然而,仍然需要用于基因递送的新的AAV载体。
发明内容
在一些方面中,本公开内容涉及用于基因治疗应用的新型AAV。在一些实施方案中,本文所述的AAV包含一种或更多种衣壳蛋白中的氨基酸变化,其赋予新的或增强的组织嗜性特性。根据一些实施方案,本文中鉴定并公开了AAV3B、AAV4和AAV5的变体,其具有有用的组织靶向特性。例如,提供了可用于转导细胞如人肝细胞(例如,存在于肝组织中)等的AAV3B的变体。提供了可用于靶向中枢神经系统(central nervous system,CNS)、心肺组织、眼组织和其他组织的细胞的AAV4和AAV5的变体。在一些实施方案中,本文所述的变体AAV靶向除了其相应的野生型AAV靶向的组织之外的组织。在一些实施方案中,AAV3B变体靶向中枢神经系统(CNS)或心脏的细胞。在一些实施方案中,AAV4变体靶向肝或肾的细胞。在一些实施方案中,AAV5变体靶向CNS、肝、脾或心脏的细胞。
在一些方面中,本公开内容提供了分离的核酸,其包含编码AAV衣壳蛋白的选自SEQ ID NO:1至47的序列。在一些实施方案中,提供了分离的核酸片段。在某些实施方案中,分离的核酸片段不编码与SEQ ID NO:98至100中任一序列相同的肽。
在一些方面中,本公开内容提供了分离的AAV衣壳蛋白,其包含选自SEQ ID NO:51至61的氨基酸序列。在一些实施方案中,分离的AAV衣壳蛋白包含选自SEQ ID NO:51至61的序列,其中所述序列中与SEQ ID NO:98所示序列的对应氨基酸不同的氨基酸由保守替换所代替。在一些实施方案中,分离的AAV衣壳蛋白包含选自SEQ ID NO:62至67的序列,其中所述序列中与SEQ ID NO:99所示序列的对应氨基酸不同的氨基酸由保守替换所代替。在一些实施方案中,分离的AAV衣壳蛋白包含选自SEQ ID NO:68至97的序列,其中所述序列中与SEQ ID NO:100所示序列的对应氨基酸不同的氨基酸由保守替换所代替。
在本公开内容的某些方面中,提供了包含任意前述分离AAV衣壳蛋白的组合物。在一些实施方案中,所述组合物还包含可药用载体。在一些实施方案中,提供了这样的组合物,其包含一种或更多种本公开内容的分离AAV衣壳蛋白和生理相容性载体。
在本公开内容的某些方面中,提供了包含任意前述分离AAV衣壳蛋白的重组AAV(rAAV)。在一些实施方案中,提供了包含rAAV的组合物。在某些实施方案中,所述包含rAAV的组合物还包含可药用载体。还提供了重组AAV,其中所述重组AAV包含一种或更多种本公开内容的分离AAV衣壳蛋白。
在本公开内容的一些方面中,提供了宿主细胞,其含有包含与启动子有效连接的选自SEQ ID NO:1至47的编码序列的核酸。在一些实施方案中,提供了包含宿主细胞和无菌细胞培养基的组合物。在一些实施方案中,提供了包含宿主细胞和冷冻保存剂的组合物。
根据本公开内容的一些方面,提供了向对象递送转基因的方法。在一些实施方案中,所述方法包括向对象施用任意前述rAAV,其中所述rAAV包含至少一种转基因,并且其中所述rAAV感染所述对象靶组织的细胞。在一些实施方案中,对象选自小鼠、大鼠、兔、狗、猫、绵羊、猪和非人灵长类。在一个实施方案中,对象是人。在一些实施方案中,所述至少一种转基因是蛋白质编码基因。在某些实施方案中,所述至少一种转基因编码小干扰核酸。在某些实施方案中,小干扰核酸是miRNA。在某些实施方案中,小干扰核酸是抑制对象中至少一种miRNA的活性的miRNA海绵或TuD RNA。在某些实施方案中,miRNA在靶组织的细胞中表达。在某些实施方案中,靶组织是骨骼肌、心、肝、胰、脑或肺。在一些实施方案中,转基因表达包含至少一个miRNA结合位点的转录物,其中所述miRNA通过与结合位点杂交而抑制除靶组织以外的组织中转基因的活性。在某些实施方案中,经静脉内、透皮、眼内、鞘内、脑内、经口、肌内、皮下、鼻内或通过吸入向对象施用rAAV。
根据本公开内容的一些方面,提供了用于产生体细胞转基因动物模型的方法。在一些实施方案中,所述方法包括向非人动物施用任一种前述rAAV,其中所述rAAV包含至少一种转基因,并且其中所述rAAV感染所述非人动物靶组织的细胞。在一些实施方案中,所述至少一种转基因是蛋白质编码基因。在某些实施方案中,所述至少一种转基因编码小干扰核酸。在一些实施方案中,所述至少一种转基因编码报告分子。在某些实施方案中,小干扰核酸是miRNA。在某些实施方案中,小干扰核酸是抑制动物中至少一种miRNA的活性的miRNA海绵或TuD RNA。在某些实施方案中,miRNA在靶组织的细胞中表达。在某些实施方案中,靶组织是骨骼肌、心、肝、胰、脑或肺。在一些实施方案中,转基因表达包含至少一个miRNA结合位点的转录物,其中所述miRNA通过与结合位点杂交而抑制除靶组织以外的组织中转基因的活性。
根据本公开内容的一些方面,提供了用于产生体细胞转基因动物模型的方法,其包括向非人动物施用任意前述rAAV,其中所述rAAV包含至少一种转基因,其中所述转基因表达包含至少一个miRNA结合位点的转录物,其中所述miRNA通过与转录物的结合位点杂交而抑制除靶组织以外的组织中转基因的活性。在一些实施方案中,转基因包含组织特异性启动子或诱导型启动子。在某些实施方案中,组织特异性启动子是肝特异性甲状腺素结合球蛋白(thyroxin binding globulin,TBG)启动子、胰岛素启动子、胰高血糖素启动子、生长抑素启动子、胰多肽(pancreatic polypeptide,PPY)启动子、突触蛋白-1(Syn)启动子、肌酸激酶(MCK)启动子、哺乳动物结蛋白(DES)启动子、α-肌球蛋白重链(a-MHC)启动子或心肌肌钙蛋白T(cardiac Troponin T,cTnT)启动子。在某些实施方案中,经静脉内、透皮、眼内、鞘内、经口、肌内、皮下、鼻内或通过吸入向动物施用rAAV。根据本公开内容的一些方面,提供了通过任意前述方法产生的体细胞转基因动物模型。
在本公开内容的另一些方面中,提供了用于产生rAAV的试剂盒。在一些实施方案中,所述试剂盒包含容纳有具有SEQ ID NO:1至47中任一序列的分离核酸的容器。在一些实施方案中,所述试剂盒还包含用于产生rAAV的说明书。在一些实施方案中,所述试剂盒还包含至少一个容纳有重组AAV载体的容器,其中所述重组AAV载体包含转基因。
在本公开内容的另一些方面中,提供了这样的试剂盒,其包含容纳有具有任意前述分离AAV衣壳蛋白的重组AAV的容器。在一些实施方案中,所述试剂盒的容器是注射器。
在另一些方面中,本公开内容涉及将基于AAV的载体作为载剂用于递送基因、治疗、预防和研究目的以及体细胞转基因动物模型开发的用途。在一些方面中,本公开内容涉及这样的AAV血清型,其已经显示出独特的组织/细胞型嗜性,并且可以在不存在载体相关毒理学的情况下以与腺病毒载体类似的水平在动物组织中实现稳定的体细胞基因转移(例如,取决于靶组织和载体剂量的高达100%的体内组织转导)。在另一些方面中,本公开内容涉及具有肝、心、骨骼肌、脑和胰组织靶向能力的AAV血清型。这些组织与广泛的人类疾病(包括多种代谢、心血管和糖尿病)有关。在一些实施方案中,所述rAAV包含至少一种转基因。所述转基因可以是导致病理状态的转基因。在一些实施方案中,所述转基因编码治疗病理状态的蛋白质。
在另一个方面中,本公开内容的新型AAV可用于用于将转基因递送至对象的方法。所述方法通过将本公开内容的rAAV施用于对象来进行,其中所述rAAV包含至少一种转基因。在一些实施方案中,所述rAAV靶向对象的预定组织。
在另一个方面中,本公开内容的AAV可用于用于产生体细胞转基因动物模型的方法。所述方法通过将本公开内容的rAAV施用于动物来进行,其中所述rAAV包含至少一种转基因,其中所述转基因导致病理状态,并且其中所述rAAV靶向动物的预定组织。
在一个实施方案中,所述rAAV含有具有选自SEQ ID NO:51至97的氨基酸序列的AAV衣壳。
所述转基因可表达许多基因,包括癌相关基因、促凋亡基因和凋亡相关基因。在一些实施方案中,所述转基因表达能够抑制癌相关基因表达的小干扰核酸。在另一些实施方案中,所述转基因表达能够抑制凋亡相关基因表达的小干扰核酸。在另一些实施方案中,所述小干扰核酸是miRNA或shRNA。根据另一些实施方案,所述转基因表达毒素,任选地其中所述毒素是DTA。在另一些实施方案中,所述转基因表达报告基因,所述报告基因任选地是报告酶(如β-半乳糖苷酶)或荧光蛋白(如GFP)。
所述转基因可表达miRNA。在另一些实施方案中,所述转基因表达miRNA海绵,其中miRNA海绵抑制动物中一种或更多种miRNA的活性。在一些实施方案中,miRNA可以是内源性miRNA,或者其可以在心、肝、骨骼肌、脑或胰组织的细胞中表达。
在一个实施方案中,AAV的靶组织是生殖腺、隔膜、心、胃、肝、脾、胰或肾。所述rAAV可转导许多不同类型的组织,例如肌纤维、鳞状上皮细胞、肾近曲或远曲小管细胞、粘膜腺细胞、血管内皮细胞或平滑肌细胞。
在一些实施方案中,所述rAAV以每个对象1010、1011、1012、1013、1014或1015个基因组拷贝的剂量施用。在一些实施方案中,所述rAAV以每千克1010、1011、1012、1013或1014个基因组拷贝的剂量施用。所述rAAV可以通过任何途径施用。例如、其在一些实施方案中可以静脉内施用(例如,通过门静脉注射)。
在一些实施方案中,所述转基因包括组织特异性启动子,例如肝特异性甲状腺素结合球蛋白(TBG)启动子、胰岛素启动子、胰高血糖素启动子、生长抑素启动子、胰多肽(PPY)启动子、突触蛋白-1(Syn)启动子、肌酸激酶(MCK)启动子、哺乳动物结蛋白(DES)启动子、α-肌球蛋白重链(a-MHC)启动子或心肌肌钙蛋白T(cTnT)启动子。
所述体细胞转基因动物模型可以是哺乳动物,例如小鼠、大鼠、兔、狗、猫、绵羊、猪、非人灵长类。
在一些实施方案中,可以向体细胞转基因动物模型施用推定的治疗剂以确定所述推定的治疗剂对动物病理状态的作用。
在另一个方面中,本公开内容是通过本文所述方法产生的体细胞转基因动物。
根据本公开内容的另一个方面,提供了用于产生rAAV的试剂盒,所述rAAV产生在预定组织中具有病理状态的体细胞转基因动物。所述试剂盒包含至少一个容纳有重组AAV载体的容器,至少一个容纳有rAAV包装组件的容器,以及用于构建和包装重组AAV的说明书。
rAAV包装组件可包括表达至少一种rep基因和/或至少一种cap基因的宿主细胞。在一些实施方案中,所述宿主细胞是293细胞。在另一些实施方案中,所述宿主细胞表达影响含有重组AAV载体的rAAV产生的至少一种辅助病毒基因产物。所述至少一种cap基因可编码靶向预定组织的来自AAV血清型的衣壳蛋白。
在另一些实施方案中,rAAV包装组件包括辅助病毒,任选地其中所述辅助病毒是腺病毒或疱疹病毒。
rAAV载体及其中的组件可包括本文所述的任何元件。例如,在一些实施方案中,所述rAAV载体包含转基因,例如本文所述的任意转基因。在一些实施方案中,所述转基因表达miRNA抑制剂(例如,miRNA海绵或TuD RNA),其中miRNA抑制剂抑制体细胞转基因动物中一种或更多种miRNA的活性。
本公开内容的每个限制可以涵盖本公开内容的多个实施方案。因此,预期本公开内容中涉及任何一个元件或元件组合的每个限制都可以包括在本公开内容的每个方面中。本公开内容在其应用中不限于在以下描述中阐述或在附图中示出的构造细节和组件布置。本公开内容能够具有其他实施方案并且能够以多种方式实践或执行。
附图说明
图1描绘了AAV 3B变体衣壳序列的比对;
图2描绘了AAV 4变体衣壳序列的比对;
图3描绘了AAV 5变体衣壳序列的比对;并且
图4描述了重组AAV转导测定的结果。
发明详述
腺相关病毒(AAV)是一种小(约26nm)的复制缺陷型非包膜病毒,其在细胞中的生长一般依赖于第二种病毒如腺病毒或疱疹病毒的存在。并不知道AAV引起疾病并诱导非常轻微的免疫应答。AAV可以感染分裂细胞和非分裂细胞二者,并且可以将其基因组并入到宿主细胞的基因组中。这些特征使得AAV成为用于创建基因治疗的病毒载体的非常有吸引力的候选物。基于血清型2的原型AAV载体为鼠和大动物模型中的无毒且稳定的基因转移提供了概念证明,但是在许多主要靶组织中表现出不良的基因转移效率。在一些方面中,本公开内容试图通过提供具有独特组织靶向能力的新型AAV来克服这个缺点,以用于基因治疗和研究应用。
在本公开内容的一些方面中,提供了具有独特组织靶向能力的新型AAV衣壳蛋白。在一些实施方案中,AAV衣壳蛋白分离自包含衣壳蛋白的AAV所靶向的组织。在一些方面中,提供了用于将转基因递送至对象靶组织的方法。所述转基因递送方法可用于基因治疗(例如,治疗疾病)或研究(例如,产生体细胞转基因动物模型)应用。
发现AAV的方法
AAV的许多生物学特征受其衣壳的影响。因此,发现新AAV的方法主要集中于分离AAV衣壳的DNA序列。腺相关病毒(AAV)潜伏生命周期的核心特征是在宿主细胞中以整合和/或附加基因组的形式持续存在。用于分离新AAV的方法包括:基于PCR的潜伏AAV DNA基因组的分子拯救、体外的在腺病毒辅助功能存在下对来自组织DNA中的潜伏前病毒基因组的感染性病毒拯救,以及由等温噬菌体Phi-29聚合酶介导的通过滚环线性扩增进行的对来自组织DNA中的环状前病毒基因组的拯救。所有的这些分离方法均利用AAV前病毒DNA基因组的潜伏期并且集中于拯救持续性病毒基因组DNA。
内源性潜伏AAV基因组在哺乳动物细胞(例如,非人类灵长类组织如肝、脾和淋巴结的细胞)中具有转录活性。不希望受理论束缚,假设为保持宿主中的AAV持久性,可能需要AAV基因的低水平转录,并且所得到的cap RNA可以用作更合适且丰富的底物以挽回用于载体开发的功能性cap序列。通过RNA检测方法(例如,RT-PCR)检测rep和cap基因转录物的可变丰度。cap基因转录物的存在和通过逆转录(reverse transcription,RT)在体外产生capRNA的cDNA的能力显著增加了用于基于PCR从组织中拯救新cap序列的模板的丰度,并增强了发现新AAV的敏感性。
通过用从具有非常低丰度的前病毒AAV基因组的组织中分离的总细胞DNA来转染细胞也可以鉴定新的cap序列。还可以用提供辅助病毒功能(例如,腺病毒)以触发和/或增强转染细胞中AAV基因转录的基因来转染细胞。本公开内容的新cap序列可以通过从转染细胞中分离cap mRNA,从mRNA产生cDNA(例如,通过RT-PCR)并对cDNA进行测序来鉴定。
分离的衣壳蛋白和编码其的核酸
分离自哺乳动物特别是非人灵长类的AAV可用于创建用于临床开发和人类基因治疗应用的基因转移载体。在一些方面中,本公开内容提供了使用本文公开的方法在多种非人灵长类组织中发现的新AAV。在分离自非人灵长类组织的病毒基因组DNA和mRNA中均发现了编码这些新AAV的衣壳蛋白的核酸。关于AAV的核酸和蛋白质序列以及其他信息列于表1和表2以及序列表中。
编码AAV衣壳蛋白的本公开内容的分离核酸包括具有如SEQ ID NO1至47中任一所示序列的任何核酸以及具有与其基本上同源之序列的任何核酸。在一些实施方案中,本公开内容提供了这样的分离核酸,其与具有如SEQ ID NO 1至47中任一所示序列的核酸基本上同源,但是不编码具有如SEQ ID NO 98至100中任一所示氨基酸序列的蛋白质。
此外,本公开内容的分离AAV衣壳蛋白包括具有如SEQ ID NO 51至98中任一所示氨基酸序列的任何蛋白质以及与其基本上同源的任何蛋白质。在一些实施方案中,本公开内容提供了这样的分离衣壳蛋白,其与具有如SEQ ID NO 98至100中任一所示序列的蛋白质基本上同源,但是不具有如SEQ ID NO 98至100中任一所示的氨基酸序列。
“同源”是指两个多核苷酸或两个多肽部分之间的百分比同一性。当涉及核酸或其片段时,术语“基本上同源”表示当与另一核酸(或其互补链)进行带有适当的核苷酸插入或缺失的最佳比对时,在约90至100%的比对序列中存在核苷酸序列同一性。当涉及多肽或其片段时,术语“基本上同源”表示当与另一多肽进行带有适当的空位、插入或缺失的最佳比对时,在约90至100%的比对序列中存在核苷酸序列同一性。术语“高度保守”意指至少80%的同一性,优选至少90%的同一性,并且更优选超过97%的同一性。在一些情况下,高度保守可指100%的同一性。同一性是本领域技术人员通过例如使用本领域技术人员已知的算法和计算机程序容易确定的。
如本文所述,使用多种公共或商业可得的多序列比对程序(例如,可通过因特网上的Web服务器访问的“Clustal W”)中的任一种来进行核酸或多肽序列之间的比对。或者,也可以使用Vector NTI实用程序。本领域中还已知有许多可用于测量核苷酸序列同一性的算法,包括上述程序中所包含的算法。作为另一个实例,可以使用BLASTN来比较多核苷酸序列,BLASTN提供了对查询序列和搜索序列之间最佳重叠区域的比对和百分比序列同一性。类似的程序可用于比较氨基酸序列,例如“Clustal X”程序、BLASTP。通常,以默认设置使用这些程序中的任一个,但是本领域技术人员可以根据需要改变这些设置。或者,本领域技术人员可以利用另一种算法或计算机程序,其提供至少如参照算法和程序所提供的同一性或比对水平。比对可用于识别两种蛋白质或肽之间的对应氨基酸。“对应氨基酸”是蛋白质或肽序列中已与另一蛋白质或肽序列的氨基酸比对的氨基酸。对应氨基酸可以相同或不同。作为不同氨基酸的对应氨基酸可称为变体氨基酸。多种AAV变体中的对应氨基酸的表列于表4至6中。
或者,对于核酸,可以通过以下过程来确定同源性:在同源区域之间形成稳定双链体的条件下使多核苷酸杂交,然后用单链特异性核酸酶消化并对经消化的片段进行大小测定。基本上同源的DNA序列可以在例如严格条件(如针对该特定体系所确定的条件)下的Southern杂交实验中鉴定。确定适当的杂交条件在本领域的技术范围内。
“核酸”序列是指DNA或RNA序列。在一些实施方案中,术语核酸涵盖包括任何已知的DNA和RNA碱基类似物的序列,所述碱基类似物例如但不限于4-乙酰基胞嘧啶、8-羟基-N6-甲基腺苷、氮丙啶基胞嘧啶、假异胞嘧啶、5-(羧基羟基-甲基)尿嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、5-羧甲基氨基甲基-2-硫尿嘧啶、5-羧甲基-氨基甲基尿嘧啶、二氢尿嘧啶、肌苷、N6-异戊烯基腺嘌呤、1-甲基腺嘌呤、1-甲基假尿嘧啶、1-甲基鸟嘌呤、1-甲基肌苷、2,2-二甲基鸟嘌呤、2-甲基腺嘌呤、2-甲基鸟嘌呤、3-甲基-胞嘧啶、5-甲基胞嘧啶、N6-甲基腺嘌呤、7-甲基鸟嘌呤、5-甲基氨基甲基尿嘧啶、5-甲氧基-氨基-甲基-2-硫尿嘧啶、β-D-甘露糖基Q核苷、5’-甲氧基羰基甲基尿嘧啶、5-甲氧基尿嘧啶、2-甲硫基-N6-异戊烯基腺嘌呤、尿嘧啶-5-氧基乙酸甲酯、尿嘧啶-5-氧基乙酸、oxybutoxosine、假尿嘧啶、Q核苷、2-硫胞嘧啶、5-甲基-2-硫尿嘧啶、2-硫尿嘧啶、4-硫尿嘧啶、5-甲基尿嘧啶、尿嘧啶-5-氧基乙酸甲酯、尿嘧啶-5-氧基乙酸、假尿嘧啶、Q核苷、2-硫胞嘧啶和2,6-二氨基嘌呤。
在一些实施方案中,分离了本公开内容的蛋白质和核酸。如本文所使用的术语“分离的”是指人工获得或产生的。如本文关于核酸所使用的术语“分离的”一般是指:(i)通过例如聚合酶链式反应(polymerase chain reaction,PCR)在体外扩增的;(ii)通过克隆重组产生的;(iii)通过切割和凝胶分离纯化的;或者(iv)通过例如化学合成法合成的。分离的核酸是可以容易地通过本领域公知的重组DNA技术操作的核酸。因此,载体中所包含的其中5’和3’限制性位点已知或者已经公开了聚合酶链式反应(PCR)引物序列的核苷酸序列被认为是分离的,但是在其天然宿主中以其天然状态存在的核酸序列并不是。分离的核酸可以是基本上纯化的,但不需要如此。例如,在克隆或表达载体中分离的核酸不是纯的,因为其可仅包含微小百分比的其所存留的细胞中的物质。然而,这样的核酸也是分离的,如该术语在本文中所使用的那样,因为其可通过本领域普通技术人员已知的标准技术容易地操作。如本文关于蛋白质或肽所使用的术语“分离的”通常是指人工获得或产生的蛋白质或肽(例如,通过化学合成,通过重组DNA技术等)。
应当理解,可以进行保守氨基酸替换以提供功能等同变体或衣壳蛋白的同源物。在一些方面,本公开内容包括导致保守氨基酸替换的序列改变。如本文所使用的保守氨基酸替换是指不改变进行氨基酸替换的蛋白质的相对电荷或大小特征的氨基酸替换。变体可以根据本领域普通技术人员已知的用于改变多肽序列的方法来制备,例如,如汇编这些方法的参考文献中所找到的,例如,Molecular Cloning:A Laboratory Manual,J.Sambrook等编,第二版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,New York,1989;或者Current Protocols in Molecular Biology,F.M.Ausubel等编,John Wiley&Sons,Inc.,New York。氨基酸的保守替换包括在以下组中的氨基酸之间进行的替换:(a)M、I、L、V;(b)F、Y、W;(c)K、R、H;(d)A、G;(e)S、T;(f)Q、N;以及(g)E、D。因此,可以对本文所公开的蛋白质和多肽的氨基酸序列进行保守氨基酸替换。
编码AAV衣壳蛋白的分离核酸的实例是具有选自SEQ ID NO:1至47的序列的核酸。编码AAV衣壳序列的分离核酸的片段可用于构建编码期望衣壳序列的核酸。片段可以具有任意适当的长度。在一些实施方案中,编码AAV衣壳序列的分离核酸的片段(部分)可用于构建编码期望衣壳序列的核酸。片段可以具有任意适当的长度(例如,至少6个、至少9个、至少18个、至少36个、至少72个、至少144个、至少288个、至少576个、至少1152个或更多个核苷酸的长度)。例如,编码第一AAV衣壳蛋白之多肽的核酸序列的片段可以用于构建编码第二AAV衣壳序列的核酸序列或者可以并入编码第二AAV衣壳序列的核酸序列中,以改变AAV衣壳的特性。在一些实施方案中,包含来自多个AAV血清型的衣壳序列片段的AAV衣壳蛋白被称为嵌合AAV衣壳。所述片段可以是不编码与SEQ ID NO:98至100中任一序列相同之肽的片段。例如,编码变体氨基酸(与已知的AAV血清型相比)的核酸序列的片段可以用于构建编码AAV衣壳序列的核酸序列或者可以并入编码AAV衣壳序列的核酸序列中,以改变AAV衣壳的特性。在一些实施方案中,与已知的AAV血清型(例如,AAV血清型3B、AAV4或AAV5)相比,编码AAV变体的核酸序列可以包含约1至约100个氨基酸变体。在一些实施方案中,与已知的AAV血清型(例如,AAV血清型3B、AAV4或AAV5)相比,编码AAV变体的核酸序列可以包含约5至约50个氨基酸变体。在一些实施方案中,与已知的AAV血清型(例如,AAV血清型3B、AAV4或AAV5)相比,编码AAV变体的核酸序列可以包含约10至约30个氨基酸变体。在一些实施方案中,与已知的AAV血清型(例如,AAV血清型3B、AAV4或AAV5)相比,编码AAV变体的核酸序列可以包含1个、或2个、或3个、或4个、5个、或6个、或7个、或8个、或9个、或10个、或11个、或12个、或13个、或14个、或15个、或16个、或17个、或18个、或19个、或20个氨基酸变体。例如,与已知的AAV血清型(例如,AAV5)相比,编码AAV变体(例如,SEQ ID NO:92)的核酸序列可以包含3个氨基酸变体。通过将包含编码变体氨基酸之区域的核酸序列的片段并入编码已知AAV血清型的核酸序列中,重组cap序列可以被构造成具有一个或更多个3氨基酸变体。所述片段可以通过任何合适的方法并入,包括使用定点诱变。因此,可以创建具有新特性的新AAV变体。
重组AAV
在一些方面中,本公开内容提供了分离的AAV。如本文关于AAV所使用的术语“分离的”是指人工获得或产生的AAV。分离的AAV可以使用重组方法产生。这种AAV在本文中称为“重组AAV”。重组AAV(rAAV)优选具有组织特异性靶向能力,以使得rAAV的转基因将被特异性递送至一个或更多个预定组织。AAV衣壳是确定这些组织特异性靶向能力的重要因素。因此,可以选择具有适合于被靶向组织之衣壳的rAAV。在一些实施方案中,rAAV包含具有如SEQ ID NO 51至97中任一所示氨基酸序列的衣壳蛋白或者具有与其基本上同源的蛋白质。
获得具有期望衣壳蛋白的重组AAV的方法是本领域公知的(参见例如US 2003/0138772),其内容通过引用整体并入本文)。通常,所述方法包括培养含有以下的宿主细胞:编码AAV衣壳蛋白的核酸序列(例如,具有如SEQ ID NO:1至47中任一所示序列的核酸)或其片段;功能性rep基因;由AAV反向末端重复(inverted terminal repeat,ITR)和转基因构成的重组AAV载体;以及允许将重组AAV载体包装到AAV衣壳蛋白中的足够的辅助功能物。在一些实施方案中,衣壳蛋白是由AAV的cap基因编码的结构蛋白。在一些实施方案中,AAV包含三种衣壳蛋白:病毒体蛋白1至3(命名为VP1、VP2和VP3),所有的这些蛋白可以由单一cap基因表达。因此,在一些实施方案中,VP1、VP2和VP3蛋白共享共同核心序列。在一些实施方案中,VP1、VP2和VP3的分子量分别为约87kDa、约72kDa和约62kDa。在一些实施方案中,翻译后,衣壳蛋白在病毒基因组周围形成球形60聚体(mer)蛋白质壳。在一些实施方案中,蛋白质壳主要包含VP3衣壳蛋白。在一些实施方案中,衣壳蛋白的功能是保护病毒基因组,递送基因组和与宿主相互作用。在一些方面中,衣壳蛋白以组织特异性方式将病毒基因组递送至宿主。在一些实施方案中,VP1和/或VP2衣壳蛋白可有助于经包装AAV的组织嗜性。在一些实施方案中,经包装AAV的组织嗜性由VP3衣壳蛋白决定。在一些实施方案中,AAV的组织嗜性通过衣壳蛋白中发生的突变而增强或改变。
在一些方面中,本公开内容描述了野生型AAV血清型的变体。在一些实施方案中,所述变体具有改变的组织嗜性。在一些实施方案中,本文所述的AAV变体包含在cap基因内的氨基酸变化(例如,替换、缺失、插入)。如上所述,所有的三种衣壳蛋白都是由单一cap基因转录的。因此,在一些实施方案中,cap基因内的氨基酸变化存在于由所述cap基因编码的所有三种衣壳蛋白中。或者,在一些实施方案中,氨基酸变化可能不存在于所有三种衣壳蛋白中。在一些实施方案中,氨基酸变化仅发生在VP1衣壳蛋白中。在一些实施方案中,氨基酸变化仅发生在VP2衣壳蛋白中。在一些实施方案中,氨基酸变化仅发生在VP3衣壳蛋白中。在一些实施方案中,AAV变体包含在cap基因中的多于一个变化。在一些实施方案中,所述多于一个变化发生在相同衣壳蛋白内(例如,在VP3内)。在一些实施方案中,所述多于一个变化发生在不同衣壳蛋白内(例如,至少一个变化在VP2中而至少一个变化在VP3中)。
在一些实施方案中,本文所述的AAV变体是AAV3B、AAV4或AAV5的变体。已知AAV3B有效地转导人肝细胞(例如,肝组织)。还已知AAV3B有效地转导癌性人肝细胞。因此,在一些实施方案中,本文所述的AAV3B变体可用于将基因治疗递送至癌性和正常的人肝细胞。已知AAV4和AAV5靶向中枢神经系统(CNS)组织、心肺组织和眼睛。因此,在一些实施方案中,本文所述的AAV4和AAV5变体可用于将基因治疗递送至CNS、心肺组织或眼睛。
应当理解,与相应的野生型AAV相比,本文所述的AAV3B、AAV4和AAV5变体可以包含在cap基因内的一个或更多个变化。因此,在一些实施方案中,本文所述的AAV3B、AAV4和AAV5变体可具有可用于将基因治疗递送至不被野生型AAV3B、AAV4或AAV5所靶向的其他组织类型的组织嗜性。在一些实施方案中,本文所述的AAV3B变体(例如,CBr-7.4、CBr-7.5、CBr-7.8)可用于将基因治疗递送至中枢神经系统(CNS)。在一些实施方案中,本文所述的AAV4变体可用于靶向肾细胞或肝细胞。在一些实施方案中,本文所述的AAV5变体可用于使基因治疗靶向肝、脾、心或脑。AAV变体及其靶组织的非限制性实例可以在表1中找到。
在一些方面中,本文所述的AAV变体可用于治疗CNS相关疾病。如本文所使用的“CNS相关疾病”是中枢神经系统的疾病或病症。CNS相关疾病可影响脊髓(例如,脊髓病)、脑(例如,脑病)或者脑和脊髓周围的组织。CNS相关疾病可以是遗传起源的,其通过遗传或体细胞突变获得。CNS相关疾病可以是心理病症或疾病,例如注意缺陷多动障碍、孤独症谱系障碍、心境障碍、精神分裂症、抑郁症、雷特综合征等。CNS相关疾病可以是自身免疫病。CNS相关疾病也可以是CNS的癌症,例如脑癌。作为癌症的CNS相关疾病可以是CNS的原发性癌症,例如星形细胞瘤、成胶质细胞瘤等,或者可以是转移到CNS组织的癌症,例如转移到脑的肺癌。CNS相关疾病的另一些非限制性实例包括帕金森病、溶酶体贮积病、缺血、神经性疼痛、肌萎缩性侧索硬化(Amyotrophic lateral sclerosis,ALS)、多发性硬化症(MultipleSclerosis,MS)和卡纳万病(Canavan disease,CD)。
在一些实施方案中,本文所述的AAV变体可用于将基因治疗递送至心细胞(例如,心脏组织)。因此,在一些实施方案中,本文所述的AAV变体可用于治疗心血管疾病。如本文所使用的“心血管疾病”是心血管系统的疾病或病症。心血管疾病可能会影响心脏、循环系统、动脉、静脉、血管和/或毛细血管。心血管疾病可以是遗传起源的,其通过遗传或体细胞突变获得。心血管疾病的非限制性实例包括风湿性心脏病、瓣膜性心脏病、高血压性心脏病、动脉瘤、动脉粥样硬化、高血压病(例如,高血压)、外周动脉疾病(peripheral arterialdisease,PAD)、缺血性心脏病、心绞痛、冠心病、冠状动脉疾病、心肌梗塞、脑血管疾病、短暂性脑缺血发作、炎性心脏病、心肌病、心包疾病、先天性心脏病、心力衰竭、中风和由美洲锥虫病(Chagas disease)引起的心肌炎。
在一些实施方案中,本文所述的AAV变体可靶向肺和/或肺部系统的组织。因此,在一些实施方案中,本文所述的AAV变体可用于治疗肺部疾病。如本文所使用的“肺部疾病”是肺部系统的疾病或病症。肺部疾病可影响肺或呼吸所涉及的肌肉。肺部疾病可以是遗传起源的,其通过遗传或过体细胞突变获得。肺部疾病可以是肺的癌症,包括但不限于非小细胞肺癌、小细胞肺癌和肺类癌肿瘤。肺部疾病的另外的非限制性实例包括急性支气管炎、急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)、石棉沉滞症、哮喘、支气管扩张、细支气管炎、闭塞性细支气管炎组织性肺炎(bronchiolitis obliteransorganizing pneumonia,BOOP)、支气管肺发育不良、棉屑沉着病、慢性支气管炎、球孢子菌病(Cocci)、慢性阻塞性肺疾病(chronic obstructive pulmonary disorder,COPD)、隐源性机化性肺炎(cryptogenic organizing pneumonia,COP)、囊性纤维化、肺气肿、汉坦病毒肺综合征、组织胞浆菌病、人偏肺病毒、过敏性肺炎、流感、淋巴管瘤病、间皮瘤、中东呼吸综合征、非结核分枝杆菌、百日咳、肺尘埃沉着病(黑肺病)、肺炎、原发性纤毛运动障碍、原发性肺动脉高压、肺动脉高压、肺纤维化、肺血管病、呼吸道合胞病毒(RespiratorySyncytial Virus,RSV)、结节病、严重急性呼吸综合征(Severe Acute RespiratorySyndrome,SARS)、矽肺、睡眠呼吸暂停、婴儿猝死综合征(Sudden Infant Death Syndrome,SIDS)和肺结核。
在一些实施方案中,本文所述的AAV变体可靶向肝组织。因此,在一些实施方案中,本文所述的AAV变体可用于治疗肝病。如本文所使用的“肝病”是肝的疾病或病症。肝病可以是遗传起源的,其通过遗传或体细胞突变获得。肝病可以是肝癌,包括但不限于肝细胞癌(hepatocelluar carcinoma,HCC)、纤维板层癌、胆管癌、血管肉瘤和肝母细胞瘤。肺部疾病的其他非限制性实例包括Alagille综合征、α1抗胰蛋白酶缺乏症、自身免疫性肝炎、胆道闭锁、肝硬化、肝囊性疾病、脂肪肝疾病、半乳糖血症、胆结石、吉尔伯特氏综合征、血色沉着病、妊娠期肝病、新生儿肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、卟啉症、瑞氏综合征、结节病、中毒性肝炎、1型糖原贮积病、酪氨酸血症、甲型、乙型、丙型病毒性肝炎、威尔逊病,和血吸虫病。
在一些实施方案中,本文所述的AAV变体可靶向肾组织。因此,在一些实施方案中,本文所述的AAV变体可用于治疗肾病。如本文所使用的“肾病”是肝的疾病或病症。肝病可以是遗传起源的,其通过遗传或体细胞突变获得。肝病可以是肾的癌症,包括但不限于肾细胞癌、透明细胞癌、1型乳头状癌、2型乳头状癌、嫌色细胞癌、嗜酸性细胞癌、集合管癌、肾盂的转移性细胞癌,和威尔姆氏肿瘤。肾病的其他非限制性实例包括:Abderhalden-Kaufmann-Lignac综合征(肾病性胱氨酸贮积症)、急性肾衰竭/急性肾损伤、急性叶性肾病、急性磷酸肾病、急性肾小管坏死、腺嘌呤磷酸核糖基转移酶缺乏、腺病毒肾炎、家族性出血性肾炎(Alport Syndrome)、淀粉样变性、血管肌脂肪瘤、镇痛剂肾病、血管紧张素抗体和局灶性节段性肾小球硬化、抗磷脂综合征、抗TNF-α治疗相关性肾小球肾炎、APOL1突变、表观性心肌皮质激素过多综合征、马兜铃酸肾病、巴尔干地方性肾病、巴特综合征、甜菜尿(Beeturia)、β-地中海贫血肾病、胆汁管型肾病、BK多瘤、C1q肾病、心肾综合征、CFHR5肾病、胆固醇栓塞、Churg-Strauss综合征、乳糜尿、塌陷性肾小球病、CMV相关的塌陷性肾小球病、先天性肾病综合征、Conorenal综合征(Mainzer-Saldino综合征或Saldino-Mainzer病)、对比剂肾病、硫酸铜中毒、皮质坏死、冷沉球蛋白血症、晶体诱发的急性肾损伤、获得性囊性肾疾病、胱氨酸尿症、致密物沉积病(MPGN 2型)、登特病(X连锁隐性肾结石)、透析不平衡综合征、糖尿病肾病、尿崩症、EAST综合征、异位输尿管、水肿、Erdheim-Chester病、法布里病、家族性低尿钙性高血钙症、范科尼综合征、弗雷泽综合征、纤维连接蛋白肾小球病、原纤维性肾小球肾炎和免疫触须样肾小球病、弗雷利综合征、局灶性节段性肾小球硬化、局灶性硬化、局灶性肾小球硬化、Galloway Mowat综合征、吉特曼综合征、肾小球疾病、肾小球管反流、葡萄糖尿、肺出血肾炎综合征、溶血性尿毒综合征(Hemolytic Uremic Syndrome,HUS)、非典型溶血性尿毒综合征(Atypical Hemolytic Uremic Syndrome,aHUS)、噬血细胞综合征、出血性膀胱炎、与阵发性睡眠性血红蛋白尿症和溶血性贫血有关的血铁黄素沉积症、肝静脉阻塞病、肝窦阻塞综合征、丙型肝炎相关性肾病、肝肾综合征、HIV相关性肾病(HIVAN)、马蹄肾(肾融合)、亨纳溃疡、醛固酮增多症、高钙血症、高钾血症、高镁血症、高钠血症、高草酸尿症、高磷血症、低钙血症、低钾血症、低钾血症诱发的肾功能障碍、低镁血症、低钠血症、低磷血症、IgA肾病、IgG4肾病、间质性膀胱炎、疼痛膀胱综合征、间质性肾炎、Ivemark综合征、肾结石、肾石病、钩端螺旋体肾病、轻链沉积病、单克隆免疫球蛋白沉积病、利德尔综合征、Lightwood-Albright综合征、脂蛋白肾小球病、锂肾中毒、LMX1B突变导致的遗传性FSGS、腰痛性血尿症、狼疮、系统性红斑狼疮、狼疮性肾病、狼疮性肾炎、莱姆病相关的肾小球肾炎、疟疾性肾病、恶性高血压、软化斑、尿道口狭窄、髓质囊性肾病、髓质海绵肾、巨输尿管症、三聚氰胺中毒和肾病、膜增生性肾小球肾炎、膜性肾病、中美洲肾病、代谢性酸中毒、代谢性碱中毒、显微镜下多发性血管炎、乳-碱综合征、微小病变性肾病、多囊性发育不良肾、多发性骨髓瘤、骨髓增生性肿瘤和肾小球病、指甲髌骨综合征、钙质沉着症、肾源性系统性纤维化、肾下垂(游走肾、肾下垂)、肾病综合征、神经源性膀胱、结节性肾小球硬化、非淋病性胡桃夹综合征、口面指综合征、直立性低血压、直立性蛋白尿、渗透性利尿、Page肾、乳头坏死、乳头肾综合征(肾缺损综合征、孤立性肾发育不良)、腹膜-肾综合征、后尿道瓣膜、感染后肾小球性肾炎、链球菌感染后肾小球性肾炎、结节性多动脉炎、多囊肾病、后尿道瓣膜、子痫前期、伴有单克隆IgG沉积的增生性肾小球肾炎(纳斯病)、蛋白尿(尿蛋白)、假性醛固酮增多症、假性甲状旁腺功能减退症、肺-肾综合征、肾盂肾炎(肾感染)、肾盂积脓、放射性肾病、复食综合征、反流性肾病、急进性肾小球肾炎、肾脓肿、肾周脓肿、肾缺如、肾动脉瘤、肾动脉狭窄、肾细胞癌、肾囊肿、伴有运动诱发的急性肾衰竭的肾低尿酸血症、肾梗死、肾性骨营养不良、肾小管性酸中毒、渗透调定点重设(Reset Osmostat)、腔静脉后输尿管、腹膜后纤维化、横纹肌溶解症、与减肥手术有关的横纹肌溶解症、类风湿性关节炎相关性肾病、结节性肾病、肾和脑的耗盐症、Schimke免疫性骨质发育不良、硬皮病肾危象、蛇形腓骨多囊肾综合征、Exner综合征、镰状细胞肾病、二氧化硅暴露和慢性肾疾病、造血细胞移植后的肾病、干细胞移植相关的肾病、薄基底膜病、良性家族性血尿、膀胱三角区炎、结节性硬化症、肾小管发育不全、肿瘤溶解综合征、尿毒症、尿毒症性视神经病变、输尿管疝、尿道肉阜、尿道狭窄、尿失禁、尿道感染、尿道梗阻、膀胱直肠瘘、膀胱输尿管反流、脑视网膜血管瘤病(VonHippel-Lindau Disease)、华法林相关肾病、韦氏肉芽肿病、伴有多血管炎的肉芽肿,和Wunderlich综合征。
在一些实施方案中,本文所述的AAV变体可用于将基因治疗递送至眼组织。因此,在一些实施方案中,本文所述的AAV变体可用于治疗眼部疾病。如本文所使用的“眼部疾病”是眼睛的疾病或病症。心血管疾病可能会影响眼睛、巩膜、角膜、前房、后房、虹膜、瞳孔、晶状体、玻璃体液、视网膜或视神经。眼部疾病可以是遗传起源的,其通过遗传或体细胞突变获得。眼部疾病和病症的非限制性实例包括但不限于:年龄相关性黄斑变性、视网膜病变、糖尿病性视网膜病变、黄斑水肿、青光眼、色素性视网膜炎和眼癌。
要在宿主细胞中培养以将rAAV载体包装在AAV衣壳中的组件可以反式地提供给宿主细胞。或者,任何一种或更多种所需组件(例如,重组AAV载体、rep序列、cap序列和/或辅助功能物)可以通过稳定的宿主细胞提供,所述稳定的宿主细胞使用本领域技术人员已知的方法而被改造成包含一种或更多种所需组件。最适当地,这种稳定的宿主细胞将包含在诱导型启动子控制下的所需组件。然而,所需组件也可以在组成型启动子的控制之下。在适用于转基因的调控元件的讨论中,本文提供了合适的诱导型和组成型启动子的实例。在另一个替代方案中,所选择的稳定的宿主细胞可以包含在组成型启动子控制下的选定组件和在一种或更多种诱导型启动子控制下的其他选定组件。例如,可以产生这样的稳定宿主细胞,其来源于293细胞(其包含在组成型启动子控制下的E1辅助功能物),但是包含在诱导型启动子控制下的rep和/或cap蛋白。另外的稳定宿主细胞也可以由本领域技术人员产生。
可以用任何合适的遗传元件(载体)将产生本公开内容的rAAV所需的重组AAV载体、rep序列、cap序列和辅助功能物递送至包装性宿主细胞中。在一些实施方案中,将编码所有三种衣壳蛋白(例如VP1、VP2和VP3)的单个核酸以单个载体递送到包装性宿主细胞中。在一些实施方案中,编码衣壳蛋白的核酸通过两个载体递送到包装性宿主细胞中;第一载体包含编码两种衣壳蛋白(例如VP1和VP2)的第一核酸,第二载体包含编码单一衣壳蛋白(例如VP3)的第二核酸。在一些实施方案中,将各自包含编码不同衣壳蛋白的核酸的三种载体递送至包装性宿主细胞中。所选择的遗传元件可以通过任何合适的方法递送,包括本文所述的那些。用于构建本公开内容的任意实施方案的方法对于核酸操作技术人员是已知的,并且包括遗传工程、重组工程和合成技术。参见例如Sambrook等,Molecular Cloning:ALaboratory Manual,Cold Spring Harbor Press,Cold Spring Harbor,N.Y.。类似地,产生rAAV病毒体的方法是公知的,并且合适方法的选择不是对本公开内容的限制。参见例如K.Fisher等,J.Virol.,70:520-532(1993)和美国专利No.5,478,745。
在一些实施方案中,重组AAV可以使用三重转染方法(详细描述于美国专利No.6,001,650中)来产生。通常,重组AAV通过用待包装到AAV颗粒中的重组AAV载体(包含转基因)、AAV辅助功能载体和附属功能载体转染宿主细胞而产生。AAV辅助功能载体编码“AAV辅助功能”序列(例如rep和cap),其反式地起作用以进行高效的AAV复制和包封。优选地,AAV辅助功能载体支持有效的AAV载体产生而不产生任何可检测的野生型AAV病毒体(例如,含有功能性rep和cap基因的AAV病毒体)。适用于本公开内容的载体的非限制性实例包括美国专利No.6,001,650中描述的pHLP19和美国专利No.6,156,303中描述的pRep6cap6载体,二者的全部内容通过引用并入本文。附属功能载体编码AAV复制所依赖的非AAV源的病毒和/或细胞功能的核苷酸序列(例如“附属功能”)。附属功能包括AAV复制所需的那些功能,包括但不限于参与AAV基因转录激活、阶段特异性AAV mRNA剪接、AAV DNA复制、cap表达产物合成和AAV衣壳组装的部分。基于病毒的附属功能可以从已知的任意辅助病毒(如腺病毒、疱疹病毒(除1型单纯疱疹病毒之外)和痘苗病毒)中得到。
在一些方面中,本公开内容提供了经转染的宿主细胞。术语“转染”用于指细胞摄入外来DNA,当外源DNA被引入细胞膜内时,则细胞已被“转染”。许多转染技术是本领域公知的。参见例如Graham等(1973)Virology,52:456;Sambrook等(1989)Molecular Cloning,alaboratory manual,Cold Spring Harbor Laboratories,New York;Davis等(1986)BasicMethods in Molecular Biology,Elsevier;以及Chu等(1981)Gene13:197。这样的技术可以用于将一种或更多种外源核酸(如核苷酸整合载体和其他核酸分子)引入合适的宿主细胞中。
“宿主细胞”是指任何容纳有或能够容纳目的物质的细胞。宿主细胞通常是哺乳动物细胞。宿主细胞可以用作AAV辅助构建体、AAV小基因质粒、附属功能载体或与重组AAV产生相关的其他转移DNA的接受者。该术语包括已经被转染的原始细胞的后代。因此,本文所使用的“宿主细胞”可以指已经用外源DNA序列转染过的细胞。应当理解,由于自然、偶然或故意突变,单个亲代细胞的后代在形态方面或者在基因组或总DNA互补物方面可能不一定与原始亲本完全相同。
如本文所使用的术语“细胞系”是指在体外能够持续或延长生长和分裂的细胞群。通常,细胞系是来源于单个祖细胞的克隆群体。在本领域中还已知,在这种克隆群体的储存或转移期间,核型可以发生自发或诱导的变化。因此,来源于所提及的细胞系的细胞可能与祖先细胞或培养物不完全相同,并且所提及的细胞系包括这些变体。
如本文所使用的术语“重组细胞”是指已引入导致生物活性多肽转录或生物活性核酸(如RNA)产生的外源DNA片段(例如DNA片段)的细胞。
还可以用向AAV提供辅助功能物的载体(例如,辅助载体)来转染细胞。提供辅助功能物的载体可以提供腺病毒功能物,包括例如E1a、E1b、E2a、E4ORF6。提供这些功能物的腺病毒基因的序列可以从任何已知的腺病毒血清型获得,例如血清型2、3、4、7、12和40,并且还包括本领域已知的任何目前已鉴定的人类型。因此,在一些实施方案中,所述方法包括用表达AAV复制、AAV基因转录和/或AAV包装所需的一个或更多个基因的载体来转染细胞。
如本文所使用的术语“载体”包括当与适当的控制元件相关联时能够复制并且可以在细胞之间转移基因序列的任何遗传元件,例如质粒、噬菌体、转座子、粘粒、染色体、人造染色体、病毒、病毒体等。因此,该术语包括克隆和表达载剂以及病毒载体。在一些实施方案中,预期有用的载体是其中待转录核酸片段位于启动子的转录控制下的那些载体。“启动子”是指被细胞的合成机器或引入的合成机器所识别的引发基因特异性转录所需的DNA序列。术语“有效定位”,“控制下”或“转录控制下”是指启动子位于与核酸相关的正确位置和取向上以控制RNA聚合酶起始和基因的表达。术语“表达载体或构建体”是指含有其中部分或全部核酸编码序列能够被转录的核酸的任何类型的遗传构建体。在一些实施方案中,表达包括核酸的转录,例如,由经转录的基因产生生物活性多肽产物或抑制性RNA(例如,shRNA、miRNA、miRNA抑制物)。
在一些情况下,使用本领域公知的方法,分离的衣壳基因可以用于构建和包装重组AAV,以确定与由该基因编码的衣壳蛋白相关的功能特征。例如,分离的衣壳基因可以用于构建和包装包含报告基因(例如,B-半乳糖苷酶、GFP、萤光素酶等)的重组AAV(rAAV)。然后可以将rAAV递送至动物(例如,小鼠),并且新的分离衣壳基因的组织靶向特性可以通过检查报告基因在动物的多个组织(例如心脏、肝、肾)中的表达来确定。本文中公开了用于表征新的分离衣壳基因的另一些方法,并且还有一些方法是本领域公知的。
用于将重组载体包装在期望AAV衣壳中以产生本公开内容的rAAV的上述方法并不意在限制,并且其他合适的方法对于本领域技术人员将是明显的。
重组AAV载体
本公开内容的“重组AAV(rAAV)载体”通常至少由转基因及其调控序列以及5’和3’AAV反向末端重复(ITR)构成。将这种重组AAV载体包装入衣壳蛋白并递送至所选择的靶细胞。在一些实施方案中,转基因是与载体序列异源的核酸序列,其编码目的多肽、蛋白质、功能性RNA分子(例如,miRNA、miRNA抑制物)或其他基因产物。核酸编码序列以允许在靶组织的细胞中进行转基因转录、翻译和/或表达的方式与调控组件有效连接。
载体的AAV序列通常包含顺式作用的5’和3’反向末端重复序列(参见例如B.J.Carter在″Handbook of Parvoviruses″中,编,P.Tijsser,CRC Press,第155 168页(1990))。ITR序列的长度为约145bp。优选地,在分子中使用基本上整个编码ITR的序列,但是对这些序列的某种程度的微小修饰是允许的。修饰这些ITR序列的能力在本技术领域内(参见例如,如Sambrook等″Molecular Cloning.A Laboratory Manual″,第2版,ColdSpring Harbor Laboratory,New York(1989);以及K.Fisher等,J Virol.,70:520532(1996)的文本)。本公开内容中使用的这种分子的实例是含有转基因的“顺式作用”质粒,其中所选择的转基因序列和相关调控元件的侧翼是5’和3’AAV ITR序列。AAV ITR序列可以由任何已知的AAV获得,包括目前已鉴定的哺乳动物AAV类型。
在一些实施方案中,本公开内容的rAAV是假型rAAV。假型化是与外来病毒包膜蛋白组合来产生病毒或病毒载体的过程。其结果是假型病毒颗粒。利用这种方法,外来病毒包膜蛋白可以用于改变病毒颗粒的宿主嗜性或者提高/降低病毒颗粒的稳定性。在一些方面中,假型rAAV包含来自两种或更多种不同AAV的核酸,其中来自一种AAV的核酸编码衣壳蛋白,并且至少一种其他AAV的核酸编码其他病毒蛋白和/或病毒基因组。在一些实施方案中,假型rAAV是指包含一种AAV血清型的反向末端重复序列(ITR)和不同AAV血清型的衣壳蛋白的AAV。例如,包含血清型X的ITR并以Y蛋白壳体化的假型AAV载体将被称为AAVX/Y(例如,AAV2/1具有AAV2的ITR和AAV1的衣壳)。在一些实施方案中,假型rAAV可用于将来自一种AAV血清型的衣壳蛋白的组织特异性靶向能力与来自另一种AAV血清型的病毒DNA相组合,从而允许将转基因靶向递送至靶组织。
除了以上确定的关于重组AAV载体的主要元件之外,所述载体还包含必需的常规控制元件,其与转基因以允许其在经质粒载体转染或经本公开内容产生的病毒转染的细胞中进行转录、翻译和/或表达的方式有效连接。如本文所使用的“有效连接”序列包括与目的基因邻接的表达控制序列和以反式方式或在一定距离处作用以控制目的基因的表达控制序列二者。
表达控制序列包括适当的转录起始、终止、启动子和增强子序列;有效的RNA加工信号,例如剪接和聚腺苷酸化(polyA)信号;稳定细胞质mRNA的序列;提高翻译效率的序列(例如,Kozak共有序列);提高蛋白质稳定性的序列;以及在需要时提高编码产物分泌的序列。许多表达控制序列(包括天然的、组成型的、诱导型的和/或组织特异性的启动子)是本领域已知的并且可以使用。
如本文所使用的,当核酸序列(例如,编码序列)和调控序列以这样的方式共价连接,以使得将核酸序列的表达或转录置于调控序列的影响或控制下时,则认为它们被“有效”连接。如果期望将核酸序列翻译成功能性蛋白质,则如果诱导5’调控序列中的启动子导致编码序列转录,并且如果两个DNA序列之间的接头性质(1)不导致移码突变引入,(2)不干扰启动子区指导编码序列转录的能力,并且(3)不干扰相应RNA转录物翻译成蛋白质的能力,则两个DNA序列被认为是有效连接。因此,如果启动子区能够影响该DNA序列的转录,以使得所得转录物可被翻译成期望蛋白质或多肽,则启动子区与核酸序列有效连接。类似地,当两个或更多个编码区以这样的方式连接,以使得其来自共同启动子的转录导致两个或更多个已在框内翻译的蛋白质表达时,则它们被有效连接。在一些实施方案中,有效连接的编码序列产生融合蛋白。在一些实施方案中,有效连接的编码序列产生功能性RNA(例如,shRNA、miRNA、miRNA抑制物)。
对于编码蛋白质的核酸,一般在转基因序列之后和在3’AAV ITR序列之前插入聚腺苷酸化序列。可用于本公开内容的rAAV构建体还可以包含内含子,期望其位于启动子/增强子序列和转基因之间。一种可能的内含子序列来自SV-40,并且被称为SV-40T内含子序列。另一种可以使用的载体元件是内部核糖体进入位点(internal ribosome entry site,IRES)。IRES序列用于从单个基因转录物中产生多于一种的多肽。IRES序列用于产生包含多于一条多肽链的蛋白质。这些和其他常见载体元件的选择是常规的,并且许多这样的序列是可用的[参见例如Sambrook等和其中所引用的参考文献,例如在3.18、3.26和16.1716.27页中;以及Ausubel等,Current Protocols in Molecular Biology,John Wiley&Sons,New York,1989]。在一些实施方案中,口蹄疫病毒2A序列包括在多蛋白中;这是一种显示出介导多蛋白切割的小肽(长度约18个氨基酸)(Ryan,M D等,EMBO,1994;4:928-933;Mattion,N M等,J Virology,1996年11月,第8124-8127页;Furler,S等,Gene Therapy,2001;8:864-873;以及Halpin,C等,The Plant Journal,1999;4:453-459)。先前已经在包含质粒和基因治疗载体(AAV和逆转录病毒)的人造系统中证明了2A序列的切割活性(Ryan,M D等,EMBO,1994;4:928-933;Mattion,N M等,J Virology,1996年11月,第8124-8127页;Furler,S等,Gene Therapy,2001;8:864-873;以及Halpin,C等,The Plant Journal,1999;4:453-459;de Felipe,P等,Gene Therapy,1999;6:198-208;de Felipe,P等,Human GeneTherapy,2000;11:1921-1931.;以及Klump,H等,Gene Therapy,2001;8:811-817)。
在宿主细胞中进行基因表达所需的调控序列的确切性质可以在物种、组织或细胞类型之间变化,但是一般应包含(在必要时)分别涉及转录和翻译起始的5’非转录序列和5’非翻译序列,例如TATA盒、加帽序列、CAAT序列、增强子元件等。特别地,这种5’非转录调控序列将包含启动子区,其包含用于有效连接的基因的转录控制的启动子序列。根据需要,调控序列还可以包含增强子序列或上游激活子序列。本公开内容的载体可以任选地包含5’前导或信号序列。适当载体的选择和设计在本领域普通技术人员的能力和判断之内。
组成型启动子的实例包括但不限于逆转录病毒劳氏肉瘤病毒(Rous sarcomavirus,RSV)LTR启动子(任选地带有RSV增强子)、巨细胞病毒(CMV)启动子(任选地带有CMV增强子)[参见例如Boshart等,Cell,41:521-530(1985)]、SV40启动子、二氢叶酸还原酶启动子、β-肌动蛋白启动子、磷酸甘油激酶(PGK)启动子和EF1α启动子[Invitrogen]。
诱导型启动子允许调控基因表达并且可以通过外源供应的化合物、环境因素(如温度)或特定生理状态(例如,急性期、细胞的特定分化状态)的存在或仅在复制细胞中存在来调控。诱导型启动子和诱导型系统可从多种商业来源获得,包括但不限于Invitrogen、Clontech和Ariad。已经描述了许多其他系统,并且可以由本领域技术人员容易地选择。由外源供应启动子调控的诱导型启动子的实例包括锌诱导型绵羊金属硫蛋白(MT)启动子、地塞米松(Dex)诱导型小鼠乳腺肿瘤病毒(mouse mammary tumor virus,MMTV)启动子、T7聚合酶启动子系统(WO 98/10088)、蜕皮激素昆虫启动子(No等,Proc.Natl.Acad.Sci.USA,93:3346-3351(1996))、四环素阻遏型系统(Gossen等,Proc.Natl.Acad.Sci.USA,89:5547-5551(1992))、四环素诱导型系统(Gossen等,Science,268:1766-1769(1995),还参见Harvey等,Curr.Opin.Chem.Biol.,2:512-518(1998))、RU486诱导型系统(Wang等,Nat.Biotech.,15:239-243(1997)和Wang等,Gene Ther.,4:432-441(1997))以及雷帕霉素诱导型系统(Magari等,J.Clin.Invest.,100:2865-2872(1997))。在本文中可用的另一些类型的诱导型启动子是受特定生理状态(例如,温度、急性期、细胞的特定分化状态或仅在复制细胞中)调控的启动子。
在另一个实施方案中,将使用转基因的天然启动子。当期望转基因的表达应当模拟天然表达时,天然的启动子可以是优选的。当转基因的表达必须在时间上或发育上、或者以组织特异性方式、或者响应特定的转录刺激来进行调控时,可以使用天然启动子。在另一个实施方案中,也可以使用其他天然表达控制元件来模拟天然表达,例如增强子元件、聚腺苷酸化位点或Kozak共有序列。
在一些实施方案中,调控序列赋予组织特异性基因表达能力。在一些情况下,组织特异性调控序列结合组织特异性转录因子,后者以组织特异性方式诱导转录。这样的组织特异性调控序列(例如,启动子、增强子等)是本领域公知的。示例性组织特异性调控序列包括但不限于以下的组织特异性启动子:肝特异性甲状腺素结合球蛋白(TBG)启动子、胰岛素启动子、胰高血糖素启动子、生长抑素启动子、胰多肽(PPY)启动子、突触蛋白-1(Syn)启动子、肌酸激酶(MCK)启动子、哺乳动物结蛋白(DES)启动子、α-肌球蛋白重链(a-MHC)启动子或心肌肌钙蛋白T(cTnT)启动子。其他示例性启动子包括β-肌动蛋白启动子、乙型肝炎病毒核心启动子(Sandig等,Gene Ther.,3:1002-9(1996))、甲胎蛋白(AFP)启动子(Arbuthnot等,Hum.Gene Ther.,7:1503-14(1996))、骨骨钙素启动子(Stein等,Mol.Biol.Rep.,24:185-96(1997))、骨涎蛋白启动子(Chen等,J.Bone Miner.Res.,11:654-64(1996))、CD2启动子(Hansal等,J.Immunol.,161:1063-8(1998))、免疫球蛋白重链启动子、T细胞受体α链启动子、神经元如神经元特异性烯醇化酶(neuron-specific enolase,NSE)启动子(Andersen等,Cell.Mol.Neurobiol.,13:503-15(1993))、神经丝轻链基因启动子(Piccioli等,Proc.Natl.Acad.Sci.USA,88:5611-5(1991))和神经元特异性vgf基因启动子(Piccioli等,Neuron,15:373-84(1995))等,其对于本领域技术人员将是显然的。
在一些实施方案中,将一种或更多种miRNA的一个或更多个结合位点并入rAAV载体的转基因中,以抑制在具有转基因的对象的一个或更多个组织中的转基因表达。本领域技术人员将理解,可以选择结合位点从而以组织特异性方式控制转基因的表达。例如,可以将肝特异性miR-122的结合位点并入转基因中以抑制该转基因在肝中的表达。mRNA中的靶位点可以在5’UTR、3’UTR或编码区中。通常,靶位点在mRNA的3’UTR中。此外,转基因可以被设计为使得多个miRNA通过识别相同或多个位点来调控mRNA。多个miRNA结合位点的存在可导致多个RISC的共同作用并提供高效的表达抑制。靶位点序列可以包含总共5至100、10至60或更多个核苷酸。靶位点序列可以包含靶基因结合位点序列的至少5个核苷酸。
重组AAV载体:转基因编码序列
rAAV载体的转基因序列的组成将取决于所得载体所用的用途。例如,一种类型的转基因序列包括报告序列,其在表达后产生可检测的信号。在另一个实例中,转基因编码治疗性蛋白质或治疗性功能性RNA。在另一个实例中,转基因编码旨在用于研究目的(例如,用于产生具有转基因的体细胞转基因动物模型,例如,用于研究转基因产物的功能)的蛋白质或功能性RNA。在另一个实例中,转基因编码旨在用于产生疾病的动物模型的蛋白质或功能性RNA。合适的转基因编码序列对于本领域技术人员将是显然的。
可以在转基因中提供的报告序列包括但不限于编码以下的DNA序列:β-内酰胺酶、β-半乳糖苷酶(LacZ)、碱性磷酸酶、胸苷激酶、绿色荧光蛋白(GFP)、氯霉素乙酰转移酶(CAT)、萤光素酶和本领域公知的其他酶。当与驱动其表达的调控元件关联时,报告序列提供可通过常规方法检测的信号,包括酶、放射照相、比色、荧光或其他光谱测定、荧光活化细胞分选测定和免疫测定(包括酶联免疫吸附测定(enzyme linked immunosorbent assay,ELISA)、放射免疫测定(radioimmunoassay,RIA)和免疫组织化学)。例如,当标记序列是LacZ基因时,携带该信号的载体的存在通过β-半乳糖苷酶活性的测定来检测。当转基因是绿色荧光蛋白或萤光素酶时,携带该信号的载体可以通过发光计中的颜色或光产生来经视觉测量。这样的报告因子可例如用于验证rAAV的组织特异性靶向能力和组织特异性启动子调节活性。
在一些方面,本公开内容提供了用于预防或治疗哺乳动物中一种或更多种遗传缺陷或功能障碍的方法的rAAV载体,所述遗传缺陷或功能障碍例如,哺乳动物中的多肽缺乏或多肽过量,并且特别是用于治疗或减轻人(其表现出与细胞和组织中的这样的多肽缺陷相关的一种或更多种病症)中的缺陷的严重性或程度。该方法包括将可药用载体中编码一种或更多种治疗性肽、多肽、siRNA、microRNA、反义核苷酸等的rAAV载体以足以治疗患有这样的病症的对象中之缺陷或病症的量和时间段来施用于对象。
因此,本公开内容包括递送编码一种或更多种肽、多肽或蛋白质的rAAV载体,其可用于治疗或预防哺乳动物对象中的疾病状态。示例性治疗性蛋白质包括选自以下的一种或更多种多肽:生长因子、白细胞介素、干扰素、抗凋亡因子、细胞因子、抗糖尿病因子、抗凋亡剂、凝血因子、抗肿瘤因子。治疗性蛋白质的其他非限制性实例包括BDNF、CNTF、CSF、EGF、FGF、G-SCF、GM-CSF、促性腺激素、IFN、IFG-1、M-CSF、NGF、PDGF、PEDF、TGF、VEGF、TGF-B2、TNF、催乳素、促生长素、XIAP1、IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-10(187A)、病毒性IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17和IL-18。
rAAV载体可以包含待转移到对象以治疗与基因表达减少、缺乏基因表达或基因功能障碍有关的疾病的基因。示例性基因和相关疾病状态包括但不限于:与1A型糖原贮积缺陷有关的葡萄糖-6-磷酸酶;与Pepck缺陷有关的磷酸烯醇丙酮酸羧激酶;与半乳糖血症有关的半乳糖-1磷酸尿苷转移酶;与苯丙酮尿症有关的苯丙氨酸羟化酶;与枫糖尿症有关的支链α-酮酸脱氢酶;与1型酪氨酸血症有关的延胡索酰乙酰乙酸水解酶;与甲基丙二酸血症有关的甲基丙二酰辅酶A变位酶;与中链乙酰辅酶A缺陷有关的中链酰基辅酶A脱氢酶;与鸟氨酸转氨甲酰酶缺陷有关的鸟氨酸转氨甲酰酶;与瓜氨酸血症有关的精氨琥珀酸合成酶;与家族性高胆固醇血症有关的低密度脂蛋白受体蛋白;与克里格勒-纳贾尔病有关的UDP-葡糖醛酸基转移酶;与严重联合免疫缺陷病有关的腺苷脱氨酶;与痛风和莱施-奈恩综合征有关的次黄嘌呤鸟嘌呤磷酸核糖转移酶;与生物素酶缺陷有关的生物素酶;与戈谢病有关的β-葡糖脑苷脂酶;与Sly综合征有关的β-葡糖苷酸酶;与脑肝肾综合征(Zellwegersyndrome)有关的过氧化物酶体膜蛋白70kDa;与急性间歇性卟啉症有关的胆色素原脱氨酶;用于治疗α-1抗胰蛋白酶缺陷(肺气肿)的α-1抗胰蛋白酶;用于治疗由于地中海贫血或由于肾衰竭引起的贫血的红细胞生成素;用于治疗缺血性疾病的血管内皮生长因子、血管生成素-1和成纤维细胞生长因子;用于治疗如例如动脉粥样硬化、血栓形成或栓塞中可见的闭塞血管的血栓调节蛋白和组织因子途径抑制剂;用于治疗帕金森病的芳香族氨基酸脱羧酶(aromatic amino acid decarboxylase,AADC)和酪氨酸羟化酶(tyrosinehydroxylase,TH);用于治疗充血性心力衰竭的β肾上腺素能受体、受磷蛋白的反义或突变形式、肌(内)质网腺苷三磷酸酶-2(SERCA2)和心脏腺苷酸环化酶;用于治疗多种癌症的肿瘤抑制基因如p53;例如用于治疗炎性和免疫疾病和癌症的多种白细胞介素之一的细胞因子;用于治疗肌肉萎缩症的肌养蛋白或小肌养蛋白和肌营养相关蛋白或小肌营养相关蛋白;以及用于治疗糖尿病的胰岛素。
在一些实施方案中,本公开内容涉及包含编码可用于治疗与中枢神经系统(CNS)有关的病症、疾病或病患之蛋白质或功能性RNA的核酸的AAV。以下是与CNS疾病有关的基因的非限制性列表:与阿尔茨海默病有关的DRD2、GRIA1、GRIA2、GRIN1、SLC1A1、SYP、SYT1、CHRNA7、3Rtau/4rTUS、APP、BAX、BCL-2、GRIK1、GFAP、IL-1、AGER;与帕金森病有关的UCH-L1、SKP1、EGLN1、Nurr-1、BDNF、TrkB、gstm1、S106β;与亨廷顿病有关的IT15、PRNP、JPH3、TBP、ATXN1、ATXN2、ATXN3、Atrophin 1、FTL、TITF-1;与弗里德赖希共济失调有关的FXN;与卡纳万病有关的ASPA;与肌营养不良有关的DMD;以及与脊髓性肌萎缩有关的SMN1、UBE1、DYNC1H1。在一些实施方案中,本公开内容涉及包含表达一种或更多种前述基因或其片段的核酸的重组AAV。在一些实施方案中,本公开内容涉及包含表达一种或更多种功能性RNA的核酸的重组AAV,所述功能性RNA抑制一种或更多种前述基因的表达。
在一些实施方案中,本公开内容涉及编码可用于治疗与心血管系统有关的病症、疾病或病患之蛋白质或功能性RNA的核酸。以下是与心血管疾病有关的基因的非限制性列表:VEGF、FGF、SDF-1、连接蛋白40、连接蛋白43、SCN4a、HIF1α、SERCa2a、ADCY1和ADCY6。在一些实施方案中,本公开内容涉及包含表达一种或更多种前述基因或其片段的核酸的重组AAV。在一些实施方案中,本公开内容涉及包含表达一种或更多种功能性RNA的核酸的重组AAV,所述功能性RNA抑制一种或更多种前述基因的表达。
在一些实施方案中,本公开内容涉及包含编码可用于治疗与肺系统有关的病症、疾病或病患之蛋白质或功能性RNA之核酸的AAV。以下是与肺部疾病有关的基因的非限制性列表:TNFα、TGFβ1、SFTPA1、SFTPA2、SFTPB、SFTPC、HPS1、HPS3、HPS4、ADTB3A、IL1A、IL1B、LTA、IL6、CXCR1和CXCR2。在一些实施方案中,本公开内容涉及包含表达一种或更多种前述基因或其片段的核酸的重组AAV。在一些实施方案中,本公开内容涉及包含表达一种或更多种功能性RNA的核酸的重组AAV,所述功能性RNA抑制一种或更多种前述基因的表达。
在一些实施方案中,本公开内容涉及包含编码可用于治疗与肝有关的病症、疾病或病患之蛋白质或功能性RNA的核酸的AAV。以下是与肝疾病有关的基因的非限制性列表:α1-AT、HFE、ATP7B、延胡索酰乙酰乙酸水解酶(FAH)、葡萄糖-6-磷酸酶、NCAN、GCKR、LYPLAL1和PNPLA3。在一些实施方案中,本公开内容涉及包含表达一种或更多种前述基因或其片段的核酸的重组AAV。在一些实施方案中,本公开内容涉及包含表达一种或更多种功能性RNA的核酸的重组AAV,所述功能性RNA抑制一种或更多种前述基因的表达。
在一些实施方案中,本公开内容涉及包含编码可用于治疗与肾有关的病症、疾病或病患之蛋白质或功能性RNA的核酸的AAV。以下是与肾疾病有关的基因的非限制性列表:
PKD1,PKD2,PKHD1,NPHS1,NPHS2,PLCE1,CD2AP,LAMB2,TRPC6,WT1,LMX1B,SMARCAL1,COQ2,PDSS2,SCARB3,FN1,COL4A5,COL4A6,COL4A3,COL4A4,FOX1C,RET,UPK3A,BMP4,SIX2,CDC5L,USF2,ROBO2,SLIT2,EYA1,MYOG,SIX1,SIX5,FRAS1,FREM2,GATA3,KAL1,PAX2,TCF2,和SALL1。在一些实施方案中,本公开内容涉及包含表达一种或更多种前述基因或其片段的核酸的重组AAV。在一些实施方案中,本公开涉及包含表达一种或更多种功能性RNA的核酸的重组AAV,所述功能性RNA抑制一种或更多种前述基因的表达。
在一些实施方案中,本公开内容涉及包含编码可用于治疗与眼有关的病症、疾病或病患之蛋白质或功能性RNA的核酸的AAV。以下是与眼部疾病有关的基因的非限制性列表:CFH、C3、MT-ND2、ARMS2、TIMP3、CAMK4、FMN1、RHO、USH2A、RPGR、RP2、TMCO、SIX1、SIX6、LRP12、ZFPM2、TBK1、GALC、肌纤蛋白、CYP1B1、CAV1、CAV2、optineurin和CDKN2B。在一些实施方案中,本公开内容涉及包含表达一种或更多种前述基因或其片段的核酸的重组AAV。在一些实施方案中,本公开内容涉及包含表达一种或更多种功能性RNA的核酸的重组AAV,所述功能性RNA抑制一种或更多种前述基因的表达。
本公开内容的rAAV可用于恢复在对象中表达减少、沉默或其他功能障碍的基因(例如,在患有癌症的对象中沉默的肿瘤抑制基因)的表达。本公开内容的rAAV也可以用于敲低在对象中异常表达的基因(例如,在患有癌症的对象中表达的致癌基因)的表达。在一些实施方案中,包含编码与癌症有关基因产物(例如,肿瘤抑制基因)的核酸的rAAV载体可用于通过将所述具有rAAV载体的rAAV施用于患有癌症的对象来治疗癌症。在一些实施方案中,包含编码抑制与癌症有关的基因产物(例如,致癌基因)表达的小干扰核酸(例如,shRNA、miRNA)的核酸的rAAV载体可用于通过将所述具有rAAV载体的rAAV施用于患有癌症的对象来治疗癌症。在一些实施方案中,包含编码与癌症有关的基因产物的核酸(或者抑制与癌症有关的基因表达的功能性RNA)的rAAV载体可用于研究目的,例如,用于研究癌症或用于鉴定治疗癌症的疗法。以下是已知与癌症发生有关的示例性基因(例如,致癌基因和肿瘤抑制基因)的非限制性列表:
AARS,ABCB1,ABCC4,ABI2,ABL1,ABL2,ACK1,ACP2,ACY1,ADSL,AK1,AKR1C2,AKT1,ALB,ANPEP,ANXA5,ANXA7,AP2M1,APC,ARHGAP5,ARHGEF5,ARID4A,ASNS,ATF4,ATM,ATP5B,ATP5O,AXL,BARD1,BAX,BCL2,BHLHB2,BLMH,BRAF,BRCA1,BRCA2,BTK,CANX,CAP1,CAPN1,CAPNS1,CAV1,CBFB,CBLB,CCL2,CCND1,CCND2,CCND3,CCNE1,CCT5,CCYR61,CD24,CD44,CD59,CDC20,CDC25,CDC25A,CDC25B,CDC2L5,CDK10,CDK4,CDK5,CDK9,CDKL1,CDKN1A,CDKN1B,CDKN1C,CDKN2A,CDKN2B,CDKN2D,CEBPG,CENPC1,CGRRF1,CHAF1A,CIB1,CKMT1,CLK1,CLK2,CLK3,CLNS1A,CLTC,COL1A1,COL6A3,COX6C,COX7A2,CRAT,CRHR1,CSF1R,CSK,CSNK1G2,CTNNA1,CTNNB1,CTPS,CTSC,CTSD,CUL1,CYR61,DCC,DCN,DDX10,DEK,DHCR7,DHRS2,DHX8,DLG3,DVL1,DVL3,E2F1,E2F3,E2F5,EGFR,EGR1,EIF5,EPHA2,ERBB2,ERBB3,ERBB4,ERCC3,ETV1,ETV3,ETV6,F2R,FASTK,FBN1,FBN2,FES,FGFR1,FGR,FKBP8,FN1,FOS,FOSL1,FOSL2,FOXG1A,FOXO1A,FRAP1,FRZB,FTL,FZD2,FZD5,FZD9,G22P1,GAS6,GCN5L2,GDF15,GNA13,GNAS,GNB2,GNB2L1,GPR39,GRB2,GSK3A,GSPT1,GTF2I,HDAC1,HDGF,HMMR,HPRT1,HRB,HSPA4,HSPA5,HSPA8,HSPB1,HSPH1,HYAL1,HYOU1,ICAM1,ID1,ID2,IDUA,IER3,IFITM1,IGF1R,IGF2R,IGFBP3,IGFBP4,IGFBP5,IL1B,ILK,ING1,IRF3,ITGA3,ITGA6,ITGB4,JAK1,JARID1A,JUN,JUNB,JUND,K-ALPHA-1,KIT,KITLG,KLK10,KPNA2,KRAS2,KRT18,KRT2A,KRT9,LAMB1,LAMP2,LCK,LCN2,LEP,LITAF,LRPAP1,LTF,LYN,LZTR1,MADH1,MAP2K2,MAP3K8,MAPK12,MAPK13,MAPKAPK3,MAPRE1,MARS,MAS1,MCC,MCM2,MCM4,MDM2,MDM4,MET,MGST1,MICB,MLLT3,MME,MMP1,MMP14,MMP17,MMP2,MNDA,MSH2,MSH6,MT3,MYB,MYBL1,MYBL2,MYC,MYCL1,MYCN,MYD88,MYL9,MYLK,NEO1,NF1,NF2,NFKB1,NFKB2,NFSF7,NID,NINJ1,NMBR,NME1,NME2,NME3,NOTCH1,NOTCH2,NOTCH4,NPM1,NQO1,NR1D1,NR2F1,NR2F6,NRAS,NRG1,NSEP1,OSM,PA2G4,PABPC1,PCNA,PCTK1,PCTK2,PCTK3,PDGFA,PDGFB,PDGFRA,PDPK1,PEA15,PFDN4,PFDN5,PGAM1,PHB,PIK3CA,PIK3CB,PIK3CG,PIM1,PKM2,PKMYT1,PLK2,PPARD,PPARG,PPIH,PPP1CA,PPP2R5A,PRDX2,PRDX4,PRKAR1A,PRKCBP1,PRNP,PRSS15,PSMA1,PTCH,PTEN,PTGS1,PTMA,PTN,PTPRN,RAB5A,RAC1,RAD50,RAF1,RALBP1,RAP1A,RARA,RARB,RASGRF1,RB1,RBBP4,RBL2,REA,REL,RELA,RELB,RET,RFC2,RGS19,RHOA,RHOB,RHOC,RHOD,RIPK1,RPN2,RPS6KB1,RRM1,SARS,SELENBP1,SEMA3C,SEMA4D,SEPP1,SERPINH1,SFN,SFPQ,SFRS7,SHB,SHH,SIAH2,SIVA,SIVA TP53,SKI,SKIL,SLC16A1,SLC1A4,SLC20A1,SMO,SMPD1,SNAI2,SND1,SNRPB2,SOCS1,SOCS3,SOD1,SORT1,SPINT2,SPRY2,SRC,SRPX,STAT1,STAT2,STAT3,STAT5B,STC1,TAF1,TBL3,TBRG4,TCF1,TCF7L2,TFAP2C,TFDP1,TFDP2,TGFA,TGFB1,TGFBI,TGFBR2,TGFBR3,THBS1,TIE,TIMP1,TIMP3,TJP1,TK1,TLE1,TNF,TNFRSF10A,TNFRSF10B,TNFRSF1A,TNFRSF1B,TNFRSF6,TNFSF7,TNK1,TOB1,TP53,TP53BP2,TP53I3,TP73,TPBG,TPT1,TRADD,TRAM1,TRRAP,TSG101,TUFM,TXNRD1,TYRO3,UBC,UBE2L6,UCHL1,USP7,VDAC1,VEGF,VHL,VIL2,WEE1,WNT1,WNT2,WNT2B,WNT3,WNT5A,WT1,XRCC1,YES1,YWHAB,YWHAZ,ZAP70,和ZNF9。
在一些实施方案中,本公开内容涉及包含编码与CNS相关病症有关之基因产物的核酸的rAAV载体。以下是与CNS相关病症有关的基因的非限制性列表:与阿尔茨海默病有关的DRD2、GRIA1、GRIA2、GRIN1、SLC1A1、SYP、SYT1、CHRNA7、3Rtau/4rTUS、APP、BAX、BCL-2、GRIK1、GFAP、IL-1、AGER;与帕金森病有关的UCH-L1、SKP1、EGLN1、Nurr-1、BDNF、TrkB、gstm1、S106β;与亨廷顿病有关的IT15、PRNP、JPH3、TBP、ATXN1、ATXN2、ATXN3、Atrophin 1、FTL、TITF-1;与弗里德赖希共济失调有关的FXN;与卡纳万病有关的ASPA;与肌营养不良有关的DMD;以及与脊髓性肌萎缩有关的SMN1、UBE1、DYNC1H1。
rAAV载体可以包含编码调节细胞凋亡的蛋白质或功能性RNA的核酸作为转基因。以下是与细胞凋亡有关的基因的非限制性列表,编码这些基因及其同源物产物的核酸和编码抑制这些基因及其同源物表达的小干扰核酸(例如,shRNA、miRNA)的核酸在本公开内容的某些实施方案中可用作转基因:
RPS27A,ABL1,AKT1,APAF1,BAD,BAG1,BAG3,BAG4,BAK1,BAX,BCL10,BCL2,BCL2A1,BCL2L1,BCL2L10,BCL2L11,BCL2L12,BCL2L13,BCL2L2,BCLAF1,BFAR,BID,BIK,NAIP,BIRC2,BIRC3,XIAP,BIRC5,BIRC6,BIRC7,BIRC8,BNIP1,BNIP2,BNTP3,BNIP3L,BOK,BRAF,CARD10,CARD11,NLRC4,CARD14,NOD2,NOD1,CARD6,CARD8,CARD9,CASP1,CASP10,CASP14,CASP2,CASP3,CASP4,CASP5,CASP6,CASP7,CASP8,CASP9,CFLAR,CIDEA,CIDEB,CRADD,DAPK1,DAPK2,DFFA,DFFB,FADD,GADD45A,GDNF,HRK,IGF1R,LTA,LTBR,MCL1,NOL3,PYCARD,RIPK1,RIPK2,TNF,TNFRSF10A,TNFRSF10B,TNFRSF10C,TNFRSF10D,TNFRSF11B,TNFRSF12A,TNFRSFl4,TNFRSF19,TNFRSF1A,TNFRSF1B,TNFRSF21,TNFRSF25,CD40,FAS,TNFRSF6B,CD27,TNFRSF9,TNFSF10,TNFSF14,TNFSF18,CD40LG,FASLG,CD70,TNFSF8,TNFSF9,TP53,TP53BP2,TP73,TP63,TRADD,TRAF1,TRAF2,TRAF3,TRAF4,TRAF5DRD2,GRIA1,GRIA2,GRIN1,SLC1A1,SYP,SYT1,CHRNA7,3Rtau/4rTUS,APP,BAX,BCL-2,GRIK1,GFAP,IL-1,AGER,UCH-L1,SKP1,EGLN1,Nurr-1,BDNF,TrkB,gstm1,S106β,IT15,PRNP,JPH3,TBP,ATXN1,ATXN2,ATXN3,Atrophin 1,FTL,TITF-1,FXN,ASPA,DMD,和SMN1,UBE1,DYNC1H1。
技术人员还将认识到,在编码蛋白质或多肽的转基因的情况下,可以在转基因中进行导致保守氨基酸替换的突变以提供蛋白质或多肽的功能上等同的变体或同源物。在一些方面,本公开内容包括导致转基因的保守氨基酸替换的序列改变。在一些实施方案中,转基因包含具有显性负效突变的基因。例如,转基因可以表达突变蛋白质,其与和野生型蛋白质相互作用的相同元件相互作用,从而阻断野生型蛋白质的一些方面的功能。
有用的转基因产物还包括miRNA。miRNA和其他小干扰核酸通过靶RNA转录物切割/降解或靶信使RNA(mRNA)的翻译抑制来调节基因表达。miRNA是天然表达的,通常作为最终的19至25个非翻译的RNA产物。miRNA通过与靶mRNA的3’非翻译区(UTR)的序列特异性相互作用表现出其活性。这些内源性表达的miRNA形成发夹前体,其随后被加工成miRNA双链体,并进一步被加工成“成熟”单链miRNA分子。这种成熟miRNA引导多蛋白复合物miRISC,所述miRISC根据它们与成熟miRNA的互补性来确定靶mRNA的例如在3’UTR区中的靶位点。
在所述方法的某些实施方案中,miRNA基因及其同源物的以下非限制性列表可用作转基因或用作由转基因编码的小干扰核酸(例如,miRNA海绵、反义寡核苷酸、TuD RNA)的靶标:
hsa-let-7a,hsa-let-7a*,hsa-let-7b,hsa-let-7b*,hsa-let-7c,hsa-let-7c*,hsa-let-7d,hsa-let-7d*,hsa-let-7e,hsa-let-7e*,hsa-let-7f,hsa-let-7f-1*,hsa-let-7f-2*,hsa-let-7g,hsa-let-7g*,hsa-let-7i,hsa-let-7i*,hsa-miR-1,hsa-miR-100,hsa-miR-100*,hsa-miR-101,hsa-miR-101*,hsa-miR-103,hsa-miR-105,hsa-miR-105*,hsa-miR-106a,hsa-miR-106a*,hsa-miR-106b,hsa-miR-106b*,hsa-miR-107,hsa-miR-10a,hsa-miR-10a*,hsa-miR-10b,hsa-miR-10b*,hsa-miR-1178,hsa-miR-1179,hsa-miR-1180,hsa-miR-1181,hsa-miR-1182,hsa-miR-1183,hsa-miR-1184,hsa-miR-1185,hsa-miR-1197,hsa-miR-1200,hsa-miR-1201,hsa-miR-1202,hsa-miR-1203,hsa-miR-1204,hsa-miR-1205,hsa-miR-1206,hsa-miR-1207-3p,hsa-miR-1207-5p,hsa-miR-1208,hsa-miR-122,hsa-miR-122*,hsa-miR-1224-3p,hsa-miR-1224-5p,hsa-miR-1225-3p,hsa-miR-1225-5p,hsa-miR-1226,hsa-miR-1226*,hsa-miR-1227,hsa-miR-1228,hsa-miR-1228*,hsa-miR-1229,hsa-miR-1231,hsa-miR-1233,hsa-miR-1234,hsa-miR-1236,hsa-miR-1237,hsa-miR-1238,hsa-miR-124,hsa-miR-124*,hsa-miR-1243,hsa-miR-1244,hsa-miR-1245,hsa-miR-1246,hsa-miR-1247,hsa-miR-1248,hsa-miR-1249,hsa-miR-1250,hsa-miR-1251,hsa-miR-1252,hsa-miR-l253,hsa-miR-1254,hsa-miR-1255a,hsa-miR-1255b,hsa-miR-1256,hsa-miR-1257,hsa-miR-1258,hsa-miR-1259,hsa-miR-125a-3p,hsa-miR-125a-5p,hsa-miR-125b,hsa-miR-125b-1*,hsa-miR-125b-2*,hsa-miR-126,hsa-miR-126*,hsa-miR-1260,hsa-miR-1261,hsa-miR-1262,hsa-miR-1263,hsa-miR-1264,hsa-miR-1265,hsa-miR-1266,hsa-miR-1267,hsa-miR-1268,hsa-miR-1269,hsa-miR-1270,hsa-miR-1271,hsa-miR-1272,hsa-miR-1273,hsa-miR-127-3p,hsa-miR-1274a,hsa-miR-1274b,hsa-miR-1275,hsa-miR-127-5p,hsa-miR-1276,hsa-miR-1277,hsa-miR-1278,hsa-miR-1279,hsa-miR-128,hsa-miR-1280,hsa-miR-1281,hsa-miR-1282,hsa-miR-1283,hsa-miR-1284,hsa-miR-1285,hsa-miR-1286,hsa-miR-1287,hsa-miR-1288,hsa-miR-1289,hsa-miR-129*,hsa-miR-1290,hsa-miR-1291,hsa-miR-1292,hsa-miR-1293,hsa-miR-129-3p,hsa-miR-1294,hsa-miR-1295,hsa-miR-129-5p,hsa-miR-1296,hsa-miR-1297,hsa-miR-1298,hsa-miR-1299,hsa-miR-1300,hsa-miR-1301,hsa-miR-1302,hsa-miR-1303,hsa-miR-1304,hsa-miR-1305,hsa-miR-1306,hsa-miR-1307,hsa-miR-1308,hsa-miR-130a,hsa-miR-130a*,hsa-miR-130b,hsa-miR-130b*,hsa-miR-132,hsa-miR-132*,hsa-miR-1321,hsa-miR-1322,hsa-miR-1323,hsa-miR-1324,hsa-miR-133a,hsa-miR-133b,hsa-miR-134,hsa-miR-135a,hsa-miR-135a*,hsa-miR-135b,hsa-miR-135b*,hsa-miR-136,hsa-miR-136*,hsa-miR-137,hsa-miR-138,hsa-miR-138-1*,hsa-miR-138-2*,hsa-miR-139-3p,hsa-miR-139-5p,hsa-miR-140-3p,hsa-miR-140-5p,hsa-miR-141,hsa-miR-141*,hsa-miR-142-3p,hsa-miR-142-5p,hsa-miR-143,hsa-miR-143*,hsa-miR-144,hsa-miR-144*,hsa-miR-145,hsa-miR-145*,hsa-miR-146a,hsa-miR-146a*,hsa-miR-146b-3p,hsa-miR-146b-5p,hsa-miR-147,hsa-miR-147b,hsa-miR-148a,hsa-miR-148a*,hsa-miR-148b,hsa-miR-148b*,hsa-miR-149,hsa-miR-149*,hsa-miR-150,hsa-miR-150*,hsa-miR-151-3p,hsa-miR-151-5p,hsa-miR-152,hsa-miR-153,hsa-miR-154,hsa-miR-154*,hsa-miR-155,hsa-miR-155*,hsa-miR-15a,hsa-miR-15a*,hsa-miR-15b,hsa-miR-15b*,hsa-miR-16,hsa-miR-16-1*,hsa-miR-16-2*,hsa-miR-17,hsa-miR-17*,hsa-miR-181a,hsa-miR-181a*,hsa-miR-181a-2*,hsa-miR-181b,hsa-miR-181c,hsa-miR-181c*,hsa-miR-181d,hsa-miR-182,hsa-miR-182*,hsa-miR-1825,hsa-miR-1826,hsa-miR-1827,hsa-miR-183,hsa-miR-183*,hsa-miR-184,hsa-miR-185,hsa-miR-185*,hsa-miR-186,hsa-miR-186*,hsa-miR-187,hsa-miR-187*,hsa-miR-188-3p,hsa-miR-188-5p,hsa-miR-18a,hsa-miR-18a*,hsa-miR-18b,hsa-miR-18b*,hsa-miR-190,hsa-miR-190b,hsa-miR-191,hsa-miR-191*,hsa-miR-192,hsa-miR-192*,hsa-miR-193a-3p,hsa-miR-193a-5p,hsa-miR-193b,hsa-miR-193b*,hsa-miR-194,hsa-miR-194*,hsa-miR-195,hsa-miR-195*,hsa-miR-196a,hsa-miR-196a*,hsa-miR-196b,hsa-miR-197,hsa-miR-198,hsa-miR-199a-3p,hsa-miR-199a-5p,hsa-miR-199b-5p,hsa-miR-19a,hsa-miR-19a*,hsa-miR-19b,hsa-miR-19b-1*,hsa-miR-19b-2*,hsa-miR-200a,hsa-miR-200a*,hsa-miR-200b,hsa-miR-200b*,hsa-miR-200c,hsa-miR-200c*,hsa-miR-202,hsa-miR-202*,hsa-miR-203,hsa-miR-204,hsa-miR-205,hsa-miR-206,hsa-miR-208a,hsa-miR-208b,hsa-miR-20a,hsa-miR-20a*,hsa-miR-20b,hsa-miR-20b*,hsa-miR-21,hsa-miR-21*,hsa-miR-210,hsa-miR-211,hsa-miR-212,hsa-miR-214,hsa-miR-214*,hsa-miR-215,hsa-miR-216a,hsa-miR-216b,hsa-miR-217,hsa-miR-218,hsa-miR-218-1*,hsa-miR-218-2*,hsa-miR-219-1-3p,hsa-miR-219-2-3p,hsa-miR-219-5p,hsa-miR-22,hsa-miR-22*,hsa-miR-220a,hsa-miR-220b,hsa-miR-220c,hsa-miR-221,hsa-miR-221*,hsa-miR-222,hsa-miR-222*,hsa-miR-223,hsa-miR-223*,hsa-miR-224,hsa-miR-23a,hsa-miR-23a*,hsa-miR-23b,hsa-miR-23b*,hsa-miR-24,hsa-miR-24-1*,hsa-miR-24-2*,hsa-miR-25,hsa-miR-25*,hsa-miR-26a,hsa-miR-26a-1*,hsa-miR-26a-2*,hsa-miR-26b,hsa-miR-26b*,hsa-miR-27a,hsa-miR-27a*,hsa-miR-27b,hsa-miR-27b*,hsa-miR-28-3p,hsa-miR-28-5p,hsa-miR-296-3p,hsa-miR-296-5p,hsa-miR-297,hsa-miR-298,hsa-miR-299-3p,hsa-miR-299-5p,hsa-miR-29a,hsa-miR-29a*,hsa-miR-29b,hsa-miR-29b-1*,hsa-miR-29b-2*,hsa-miR-29c,hsa-miR-29c*,hsa-miR-300,hsa-miR-301a,hsa-miR-301b,hsa-miR-302a,hsa-miR-302a*,hsa-miR-302b,hsa-miR-302b*,hsa-miR-302c,hsa-miR-302c*,hsa-miR-302d,hsa-miR-302d*,hsa-miR-302e,hsa-miR-302f,hsa-miR-30a,hsa-miR-30a*,hsa-miR-30b,hsa-miR-30b*,hsa-miR-30c,hsa-miR-30c-1*,hsa-miR-30c-2*,hsa-miR-30d,hsa-miR-30d*,hsa-miR-30e,hsa-miR-30e*,hsa-miR-31,hsa-miR-31*,hsa-miR-32,hsa-miR-32*,hsa-miR-320a,hsa-miR-320b,hsa-miR-320c,hsa-miR-320d,hsa-miR-323-3p,hsa-miR-323-5p,hsa-miR-324-3p,hsa-miR-324-5p,hsa-miR-325,hsa-miR-326,hsa-miR-328,hsa-miR-329,hsa-miR-330-3p,hsa-miR-330-5p,hsa-miR-331-3p,hsa-miR-331-5p,hsa-miR-335,hsa-miR-335*,hsa-miR-337-3p,hsa-miR-337-5p,hsa-miR-338-3p,hsa-miR-338-5p,hsa-miR-339-3p,hsa-miR-339-5p,hsa-miR-33a,hsa-miR-33a*,hsa-miR-33b,hsa-miR-33b*,hsa-miR-340,hsa-miR-340*,hsa-miR-342-3p,hsa-miR-342-5p,hsa-miR-345,hsa-miR-346,hsa-miR-34a,hsa-miR-34a*,hsa-miR-34b,hsa-miR-34b*,hsa-miR-34c-3p,hsa-miR-34c-5p,hsa-miR-361-3p,hsa-miR-361-5p,hsa-miR-362-3p,hsa-miR-362-5p,hsa-miR-363,hsa-miR-363*,hsa-miR-365,hsa-miR-367,hsa-miR-367*,hsa-miR-369-3p,hsa-miR-369-5p,hsa-miR-370,hsa-miR-371-3p,hsa-miR-371-5p,hsa-miR-372,hsa-miR-373,hsa-miR-373*,hsa-miR-374a,hsa-miR-374a*,hsa-miR-374b,hsa-miR-374b*,hsa-miR-375,hsa-miR-376a,hsa-miR-376a*,hsa-miR-376b,hsa-miR-376c,hsa-miR-377,hsa-miR-377*,hsa-miR-378,hsa-miR-378*,hsa-miR-379,hsa-miR-379*,hsa-miR-380,hsa-miR-380*,hsa-miR-381,hsa-miR-382,hsa-miR-383,hsa-miR-384,hsa-miR-409-3p,hsa-miR-409-5p,hsa-miR-410,hsa-miR-411,hsa-miR-411*,hsa-miR-412,hsa-miR-421,hsa-miR-422a,hsa-miR-423-3p,hsa-miR-423-5p,hsa-miR-424,hsa-miR-424*,hsa-miR-425,hsa-miR-425*,hsa-miR-429,hsa-miR-431,hsa-miR-431*,hsa-miR-432,hsa-miR-432*,hsa-miR-433,hsa-miR-448,hsa-miR-449a,hsa-miR-449b,hsa-miR-450a,hsa-miR-450b-3p,hsa-miR-450b-5p,hsa-miR-451,hsa-miR-452,hsa-miR-452*,hsa-miR-453,hsa-miR-454,hsa-miR-454*,hsa-miR-455-3p,hsa-miR-455-5p,hsa-miR-483-3p,hsa-miR-483-5p,hsa-miR-484,hsa-miR-485-3p,hsa-miR-485-5p,hsa-miR-486-3p,hsa-miR-486-5p,hsa-miR-487a,hsa-miR-487b,hsa-miR-488,hsa-miR-488*,hsa-miR-489,hsa-miR-490-3p,hsa-miR-490-5p,hsa-miR-491-3p,hsa-miR-491-5p,hsa-miR-492,hsa-miR-493,hsa-miR-493*,hsa-miR-494,hsa-miR-495,hsa-miR-496,hsa-miR-497,hsa-miR-497*,hsa-miR-498,hsa-miR-499-3p,hsa-miR-499-5p,hsa-miR-500,hsa-miR-500*,hsa-miR-501-3p,hsa-miR-501-5p,hsa-miR-502-3p,hsa-miR-502-5p,hsa-miR-503,hsa-miR-504,hsa-miR-505,hsa-miR-505*,hsa-miR-506,hsa-miR-507,hsa-miR-508-3p,hsa-miR-508-5p,hsa-miR-509-3-5p,hsa-miR-509-3p,hsa-miR-509-5p,hsa-miR-510,hsa-miR-511,hsa-miR-512-3p,hsa-miR-512-5p,hsa-miR-513a-3p,hsa-miR-513a-5p,hsa-miR-513b,hsa-miR-513c,hsa-miR-514,hsa-miR-515-3p,hsa-miR-515-5p,hsa-miR-516a-3p,hsa-miR-516a-5p,hsa-miR-516b,hsa-miR-517*,hsa-miR-517a,hsa-miR-517b,hsa-miR-517c,hsa-miR-518a-3p,hsa-miR-518a-5p,hsa-miR-518b,hsa-miR-518c,hsa-miR-518c*,hsa-miR-518d-3p,hsa-miR-518d-5p,hsa-miR-518e,hsa-miR-518e*,hsa-miR-518f,hsa-miR-518f*,hsa-miR-519a,hsa-miR-519b-3p,hsa-miR-519c-3p,hsa-miR-519d,hsa-miR-519e,hsa-miR-519e*,hsa-miR-520a-3p,hsa-miR-520a-5p,hsa-miR-520b,hsa-miR-520c-3p,hsa-miR-520d-3p,hsa-miR-520d-5p,hsa-miR-520e,hsa-miR-520f,hsa-miR-520g,hsa-miR-520h,hsa-miR-521,hsa-miR-522,hsa-miR-523,hsa-miR-524-3p,hsa-miR-524-5p,hsa-miR-525-3p,hsa-miR-525-5p,hsa-miR-526b,hsa-miR-526b*,hsa-miR-532-3p,hsa-miR-532-5p,hsa-miR-539,hsa-miR-541,hsa-miR-541*,hsa-miR-542-3p,hsa-miR-542-5p,hsa-miR-543,bsa-miR-544,hsa-miR-545,hsa-miR-545*,hsa-miR-548a-3p,hsa-miR-548a-5p,hsa-miR-548b-3p,hsa-miR-548b-5p,hsa-miR-548c-3p,hsa-miR-548c-5p,hsa-miR-548d-3p,hsa-miR-548d-5p,hsa-miR-548e,hsa-miR-548f,hsa-miR-548g,hsa-miR-548h,hsa-miR-548i,hsa-miR-548j,hsa-miR-548k,hsa-miR-5481,hsa-miR-548m,hsa-miR-548n,hsa-miR-548o,hsa-miR-548p,hsa-miR-549,hsa-miR-550,hsa-miR-550*,hsa-miR-551a,hsa-miR-551b,hsa-miR-551b*,hsa-miR-552,hsa-miR-553,hsa-miR-554,hsa-miR-555,hsa-miR-556-3p,hsa-miR-556-5p,hsa-miR-557,hsa-miR-558,hsa-miR-559,hsa-miR-561,hsa-miR-562,hsa-miR-563,hsa-miR-564,hsa-miR-566,hsa-miR-567,hsa-miR-568,hsa-miR-569,hsa-miR-570,hsa-miR-571,hsa-miR-572,hsa-miR-573,hsa-miR-574-3p,hsa-miR-574-5p,hsa-miR-575,hsa-miR-576-3p,hsa-miR-576-5p,hsa-miR-577,hsa-miR-578,hsa-miR-579,hsa-miR-580,hsa-miR-581,hsa-miR-582-3p,hsa-miR-582-5p,hsa-miR-583,hsa-miR-584,hsa-miR-585,hsa-miR-586,hsa-miR-587,hsa-miR-588,hsa-miR-589,hsa-miR-589*,hsa-miR-590-3p,hsa-miR-590-5p,hsa-miR-591,hsa-miR-592,hsa-miR-593,hsa-miR-593*,hsa-miR-595,hsa-miR-596,hsa-miR-597,hsa-miR-598,hsa-miR-599,hsa-miR-600,hsa-miR-601,hsa-miR-602,hsa-miR-603,hsa-miR-604,hsa-miR-605,hsa-miR-606,hsa-miR-607,hsa-miR-608,hsa-miR-609,hsa-miR-610,hsa-miR-611,hsa-miR-612,hsa-miR-613,hsa-miR-614,hsa-miR-615-3p,hsa-miR-615-5p,hsa-miR-616,hsa-miR-616*,hsa-miR-617,hsa-miR-618,hsa-miR-619,hsa-miR-620,hsa-miR-621,hsa-miR-622,hsa-miR-623,hsa-miR-624,hsa-miR-624*,hsa-miR-625,hsa-miR-625*,hsa-miR-626,hsa-miR-627,hsa-miR-628-3p,hsa-miR-628-5p,hsa-miR-629,hsa-miR-629*,hsa-miR-630,hsa-miR-631,hsa-miR-632,hsa-miR-633,hsa-miR-634,hsa-miR-635,hsa-miR-636,hsa-miR-637,hsa-miR-638,hsa-miR-639,hsa-miR-640,hsa-miR-641,hsa-miR-642,hsa-miR-643,hsa-miR-644,hsa-miR-645,hsa-miR-646,hsa-miR-647,hsa-miR-648,hsa-miR-649,hsa-miR-650,hsa-miR-651,hsa-miR-652,hsa-miR-653,hsa-miR-654-3p,hsa-miR-654-5p,hsa-miR-655,hsa-miR-656,hsa-miR-657,hsa-miR-658,hsa-miR-659,hsa-miR-660,hsa-miR-661,hsa-miR-662,hsa-miR-663,hsa-miR-663b,hsa-miR-664,hsa-miR-664*,hsa-miR-665,hsa-miR-668,hsa-miR-671-3p,hsa-miR-671-5p,hsa-miR-675,hsa-miR-7,hsa-miR-708,hsa-miR-708*,hsa-miR-7-1*,hsa-miR-7-2*,hsa-miR-720,hsa-miR-744,hsa-miR-744*,hsa-miR-758,hsa-miR-760,hsa-miR-765,hsa-miR-766,hsa-miR-767-3p,hsa-miR-767-5p,hsa-miR-768-3p,hsa-miR-768-5p,hsa-miR-769-3p,hsa-miR-769-5p,hsa-miR-770-5p,hsa-miR-802,hsa-miR-873,hsa-miR-874,hsa-miR-875-3p,hsa-miR-875-5p,hsa-miR-876-3p,hsa-miR-876-5p,hsa-miR-877,hsa-miR-877*,hsa-miR-885-3p,hsa-miR-885-5p,hsa-miR-886-3p,hsa-miR-886-5p,hsa-miR-887,hsa-miR-888,hsa-miR-888*,hsa-miR-889,hsa-miR-890,hsa-miR-891a,hsa-miR-891b,hsa-miR-892a,hsa-miR-892b,hsa-miR-9,hsa-miR-9*,hsa-miR-920,hsa-miR-921,hsa-miR-922,hsa-miR-923,hsa-miR-924,hsa-miR-92a,hsa-miR-92a-1*,hsa-miR-92a-2*,hsa-miR-92b,hsa-miR-92b*,hsa-miR-93,hsa-miR-93*,hsa-miR-933,hsa-miR-934,hsa-miR-935,hsa-miR-936,hsa-miR-937,hsa-miR-938,hsa-miR-939,hsa-miR-940,hsa-miR-941,hsa-miR-942,hsa-miR-943,hsa-miR-944,hsa-miR-95,hsa-miR-96,hsa-miR-96*,hsa-miR-98,hsa-miR-99a,hsa-miR-99a*,hsa-miR-99b,和hsa-miR-99b*。
miRNA抑制其靶向的mRNA的功能,其结果是抑制由mRNA编码的多肽的表达。因此,(部分或全部)阻断miRNA的活性(例如,使miRNA沉默)可以有效诱导或恢复表达受到抑制的多肽的表达(使多肽去阻抑)。在一个实施方案中,经由多种方法中的任一种通过抑制细胞中的miRNA活性来实现miRNA对mRNA靶标编码的多肽的去阻抑。例如,可以通过与和miRNA互补或基本上互补的小干扰核酸(例如,反义寡核苷酸、miRNA海绵、TuD RNA)杂交来实现阻断miRNA的活性,从而阻断miRNA与其靶mRNA的相互作用。如本文使用的与miRNA基本上互补的小干扰核酸是能够与miRNA杂交并阻断miRNA活性的核酸。在一些实施方案中,与miRNA基本上互补的小干扰核酸是在约1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碱基处与miRNA互补的小干扰核酸。在一些实施方案中,与miRNA基本上互补的小干扰核酸序列是在至少一个碱基处与miRNA互补的小干扰核酸序列。
“miRNA抑制剂”是阻断miRNA功能、表达和/或加工的试剂。例如,这些分子包括但不限于抑制miRNA与Drosha复合物相互作用的microRNA特异性反义、microRNA海绵、toughdecoy RNA(TuD RNA)和microRNA寡核苷酸(双链、发夹、短寡核苷酸)。如上所述,microRNA抑制剂可以由rAAV载体的转基因在细胞中表达。microRNA海绵通过互补的七聚体种子序列特异性抑制miRNA(Ebert,M.S.Nature Methods,Epub,2007年8月12日;)。在一些实施方案中,可以使用单个海绵序列使整个miRNA家族沉默。TuD RNA在哺乳动物细胞中实现特定miRNA的有效和长期抑制(参见例如Takeshi Haraguchi等,Nucleic Acids Research,2009,第37卷,第6期,e43,其涉及TuD RNA的内容通过引用并入本文)。用于使细胞中miRNA功能沉默(miRNA靶标的去阻抑)的其他方法对于本领域普通技术人员将是显然的。
在一些实施方案中,重组RNA载体的克隆能力可能受到限制,并且所期望的编码序列可能需要完全替换病毒的4.8千碱基基因组。因此,在某些情况下,大基因可能不适合用于标准重组AAV载体。技术人员将理解,在本领域中一些选择可用于克服有限的编码能力。例如,两个基因组的AAV ITR可以退火以形成头尾多联体,几乎使载体的能力加倍。插入剪接位点允许从转录物中移除ITR。用于克服有限的克隆能力的其他选择对于技术人员将是显然的。
使用基于rAAV的基因转移产生的体细胞转基因动物模型
本公开内容还涉及使用基于重组腺相关病毒(rAAV)的方法产生疾病的体细胞转基因动物模型。该方法至少部分地基于如下观察:AAV血清型及其变体在成年动物中以组织特异性方式介导有效且稳定的基因转移。将rAAV元件(衣壳、启动子、转基因产物)组合从而实现以时间和组织特异性方式表达稳定转基因的体细胞转基因动物模型。通过本公开内容的方法产生的体细胞转基因动物可用作人疾病、病理状态的有用模型和/或用于表征功能(例如,组织特异性、疾病作用)未知或未完全理解的基因的作用。例如,可用包含具有特定组织靶向能力(例如,肝、心、胰)的衣壳和具有驱动疾病涉及的基因表达的组织特异性启动子的转基因的rAAV,使动物(例如,小鼠)在不同发育阶段(例如,年龄)感染。感染后,rAAV感染靶组织的不同细胞并产生转基因的产物。
在一些实施方案中,对转基因编码区的序列进行修饰。该修饰可以改变由转基因编码的产物的功能。然后可使用本文公开的方法通过产生体细胞转基因动物模型在体内研究修饰的作用。在一些实施方案中,编码区序列的修饰是得到片段(例如,截短形式)的无义突变。在另一些情况下,修饰是导致氨基酸替换的错义突变。其他修饰是可能的并且对于技术人员将是显然的。
在一些实施方案中,转基因导致病理状态。导致病理状态的转基因是其产物在疾病或病症中发挥作用(例如,引起疾病或病症、使动物易患疾病或病症)和/或可在动物中诱导疾病或病症的基因。然后可以观察动物以评估疾病的许多方面(例如,进展、对治疗的应答等)。这些实例并不意在限制,本文公开了其他一些方面和实例并且在以下对其进行更详细地描述。
在一些方面,本公开内容提供了用于通过靶向破坏特定细胞类型来产生体细胞转基因动物模型的方法。例如,1型糖尿病模型可通过靶向破坏胰β岛来产生。在另一些实例中,靶向破坏特定细胞类型可用于评估特定细胞类型对人疾病的作用。在这方面,编码细胞毒素(例如,白喉毒素A(diphtheria toxin A,DTA))的转基因或促凋亡基因(NTR、Box等)可用作特定细胞类型的功能性消融的转基因。其他示例性转基因(其产物杀伤细胞)包括在本文公开的方法中并且对于本领域普通技术人员将是显而易见的。
在一些方面,本公开内容提供了用于产生体细胞转基因动物模型的方法,以研究基因过表达或敲低的长期影响。特定靶组织中基因的长期过表达或敲低(例如,通过shRNA、miRNA、miRNA抑制剂等)可干扰正常的代谢平衡并建立病理状态,从而产生疾病(如癌症)的动物模型。在一些方面,本公开内容提供了用于产生体细胞转基因动物模型的方法,以研究潜在致癌基因和其他基因的基因过表达或敲低的长期影响,从而研究靶组织中的肿瘤发生和基因功能。有用的转基因产物包括已知与癌症有关的蛋白质和抑制这样的蛋白质的表达小干扰核酸。本领域技术人员可以容易地选择其他合适的转基因,只要它们可用于产生组织特异性病理状态和/或疾病的动物模型。
重组AAV施用方法
可以根据本领域已知的任何合适的方法将rAAV以组合物递送至对象。可以将rAAV(优选悬浮于生理相容的载体中(例如,以组合物))施用于对象,例如,宿主动物,例如人、小鼠、大鼠、猫、狗、绵羊、兔、马、牛、山羊、猪、豚鼠、仓鼠、鸡、火鸡或非人灵长类(例如,猕猴)。在一些实施方案中,宿主动物不包括人。
将rAAV递送至哺乳动物对象的操作可以通过例如肌内注射或通过施用到哺乳动物对象的血流中来进行。可以通过注射到静脉、动脉或任何其他血管导管中来施用到血流中。在一些实施方案中,将rAAV通过分离肢体灌注(外科手术领域中公知的一种技术)施用到血流中,该方法基本上使得技术人员能够在施用rAAV病毒体之前将肢体与体循环分离。技术人员也可以使用分离肢体灌注技术的变体(描述于美国专利No.6,177,403中)将病毒体施用到分离肢体的脉管系统中以潜在地增强向肌肉细胞或组织中的转导。此外,在某些情况下,可能期望将病毒体递送至对象的CNS。“CNS”意指脊椎动物的脑和脊髓的所有细胞和组织。因此,该术语包括但不限于神经元细胞、神经胶质细胞、星形胶质细胞、脑脊液(CSF)、胞间隙、骨、软骨等。可以使用本领域已知的神经外科技术(例如,通过立体定向注射)通过用针、导管或相关装置注射到例如心室区域以及注射到纹状体(例如,纹状体的尾状核或壳核)、脊髓和神经肌肉接头或小脑小叶中,从而将重组AAV直接递送至CNS或脑(参见例如Stein等,J Virol 73:3424-3429,1999;Davidson等,PNAS 97:3428-3432,2000;Davidson等,Nat.Genet.3:219-223,1993;以及Alisky和Davidson,Hum.Gene Ther.11:2315-2329,2000)。
本公开内容的组合物可以仅包含rAAV或者与一种或更多种其他病毒组合(例如,编码具有一种或更多种不同转基因的第二rAAV)。在一些实施方案中,组合物包含1、2、3、4、5、6、7、8、9、10或更多种不同的rAAV,其各自具有一种或更多种不同的转基因。
考虑到rAAV所针对的目标,本领域技术人员可以容易地选择合适的载体。例如,一种合适的载体包括盐水,其可以用多种缓冲溶液(例如,磷酸盐缓冲盐水)进行配制。其他示例性载体包括无菌盐水、乳糖、蔗糖、磷酸钙、明胶、葡聚糖、琼脂、果胶、花生油、芝麻油和水。载体的选择不是本公开内容的限制。
任选地,本公开内容的组合物除rAAV和载体之外还可以包含其他常规药物成分,例如防腐剂或化学稳定剂。合适的示例性防腐剂包括氯丁醇、山梨酸钾、山梨酸、二氧化硫、没食子酸丙酯、对羟基苯甲酸酯、乙基香草醛、甘油、苯酚和对氯苯酚。合适的化学稳定剂包括明胶和白蛋白。
以足够的量施用rAAV以转染期望组织的细胞,并提供足够的基因转移和表达水平而没有过度的不良作用。常规和药学上可接受的施用途径包括但不限于直接递送至选定器官(例如,经门静脉递送至肝)、经口、吸入(包括鼻内和气管内递送)、眼内、静脉内、肌内、皮下、皮内、瘤内和其他亲本施用途径。如果需要的话,则可以组合施用途径。
实现特定“治疗效果”所需的rAAV病毒体的剂量(例如,基因组拷贝/每千克体重(GC/kg)的剂量单位)将根据多个因素而变化,包括但不限于:rAAV病毒体施用途径、达到治疗效果所需的基因或RNA表达水平、被治疗的特定疾病或病症以及基因或RNA产物的稳定性。本领域技术人员可以基于上述因素以及本领域公知的其他因素容易地确定用于治疗患有特定疾病或病症的患者的rAAV病毒体剂量范围。
rAAV的有效量是足以靶向感染动物、靶向期望组织的量。在一些实施方案中,rAAV的有效量是足以产生稳定的体细胞转基因动物模型的量。有效量将主要取决于例如对象的物种、年龄、重量、健康和待靶向的组织的因素,因此可以在动物和组织之间变化。例如,rAAV的有效量一般是包含约109至1016个基因组拷贝的约1ml至约100ml的溶液。在一些实施方案中,以每个对象1010、1011、1012、1013、1014或1015个基因组拷贝的剂量施用rAAV。在一些实施方案中,以每kg 1010、1011、1012、1013或1014个基因组拷贝的剂量施用rAAV。在一些情况下,约1011至1012个rAAV基因组拷贝的剂量是合适的。在某些实施方案中,1012个rAAV基因组拷贝对靶向心脏、肝和胰组织是有效的。在一些情况下,通过多剂量的rAAV产生稳定的转基因动物。
在一些实施方案中,特别是在存在高rAAV浓度(例如,约1013GC/ml或更高)的情况下,将rAAV组合物配制成减少组合物中AAV颗粒的聚集。用于减少rAAV聚集的方法是本领域公知的,并且包括例如添加表面活性剂、调节pH、调节盐浓度等(参见例如Wright FR等,Molecular Therapy(2005)12,171-178,其内容通过引用并入本文)。
可药用赋形剂和载体溶液的制剂是本领域技术人员公知的,用于在多种治疗方案中使用本文所述的特定组合物的合适给药和治疗方案的开发也是如此。
通常,这些制剂可以包含至少约0.1%或更多的活性化合物,尽管活性成分的百分比当然可以变化并且可以方便地为总制剂的重量或体积的约1%或2%至约70%或80%或更高。自然地,每种治疗上有用的组合物中的活性化合物的量可以以这样的方式准备,以使得在任何给定单位剂量的化合物中将获得合适的剂量。制备这样的药物制剂的技术人员将考虑例如溶解度、生物利用度、生物半衰期、施用途径、产品保质期以及其他药理学考虑因素,因此,多种剂量和治疗方案可能是期望的。
在某些情况下,期望经皮下、胰内、鼻内、肠外、静脉内、肌内、鞘内或经口、腹膜内或通过吸入递送本文公开的经适当配制的药物组合物中的基于rAAV的治疗性构建体。在一些实施方案中,如美国专利No.5,543,158、5,641,515和5,399,363(各自明确地通过引用整体并入本文)中所述的施用形式可用于递送rAAV。在一些实施方案中,一种优选的施用方式是通过门静脉注射。
适用于可注射用途的药物形式包括无菌水溶液或分散体和用于临时制备无菌可注射溶液或分散体的无菌粉末。分散体也可以在甘油、液态聚乙二醇及其混合物中以及在油中制备。在普通储存和使用条件下,这些制剂包含防腐剂以防止微生物生长。在许多情况下,所述形式为无菌的并且流动性达到容易注射的程度。其在制造和储存条件下必须是稳定的并且必须被保藏以免受微生物(例如细菌和真菌)的污染作用。载体可以是含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等)、其合适的混合物和/或植物油的溶剂或分散介质。可以例如通过使用包衣如卵磷脂,通过在分散体的情况下维持所需的粒径和通过使用表面活性剂来维持适当的流动性。预防微生物的作用可通过多种抗菌剂和抗真菌剂(例如,对羟基苯甲酸酯类、氯丁醇、苯酚、山梨酸、硫柳汞等)来实现。在许多情况下,优选地包括等渗剂,例如,糖或氯化钠。可注射组合物的延长吸收可通过在组合物中使用延迟吸收的试剂(例如,单硬脂酸铝和明胶)来实现。
对于施用可注射水溶液,例如,如果需要的话,溶液可以适当地进行缓冲,并且首先用足够的盐水或葡萄糖使液体稀释剂等渗。这些特定的水溶液特别适用于静脉内、肌内、皮下和腹膜内施用。在这一点上,可使用的无菌水性介质将是本领域技术人员已知的。例如,一个剂量可以溶解在1ml等渗NaCl溶液中,并且被添加到1000ml的皮下灌注流体中或者在建议的输注部位处注射(参见例如,“Remington′s Pharmaceutical Sciences”第15版,第1035至1038页和第1570至1580页)。一些剂量变化必然会根据宿主的情况而发生。无论如何,负责施用的人将确定单个宿主的合适剂量。
无菌可注射溶液通过如下制备:将所需量的活性rAAV与本文列举的多种其他成分(根据需要)并入合适的溶剂中,随后过滤灭菌。通常,通过将多种无菌活性成分并入无菌载剂中来制备分散体,所述无菌载剂包含基础分散介质和来自上述列举的那些的所需其他成分。在用于制备无菌可注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥技术,所述技术由其先前无菌过滤的溶液产生活性成分与任何另外的所期望成分的粉末。
本文公开的rAAV组合物也可以被配制成中性或盐形式。可药用盐包括与无机酸(例如,盐酸或磷酸)或者如乙酸、草酸、酒石酸、扁桃酸等这样的有机酸形成的酸加成盐(与蛋白质的游离氨基形成)。与游离羧基形成的盐也可以来源于无机碱,例如,钠、钾、铵、钙或铁氢氧化物,以及例如异丙胺、三甲胺、组氨酸、普鲁卡因等的有机碱。配制后,将以与剂量制剂相容的方式并且以治疗有效的量施用溶液。所述制剂易于以多种剂型(例如可注射溶液、药物释放胶囊等)施用。
如本文使用的“载体”包括任何和所有溶剂、分散介质、载剂、包衣、稀释剂、抗菌和抗真菌剂、等渗和吸收延迟剂、缓冲剂、载体溶液、悬浮液、胶体等。这样的介质和药剂用于药物活性物质的用途是本领域公知的。也可以将补充的活性成分并入组合物中。术语“可药用”是指当施用于宿主时不产生变应或类似不良反应的分子实体和组合物。
递送载剂(例如脂质体、纳米胶囊、微粒、微球、脂质颗粒、囊泡等)可用于将本公开内容的组合物引入合适的宿主细胞中。特别地,rAAV载体递送的转基因可以被配制成用于包封在脂质颗粒、脂质体、囊泡、纳米球或纳米颗粒等中递送。
这样的制剂对于引入本文公开的核酸或rAAV构建体的可药用制剂可以是优选的。脂质体的形成和使用是本领域技术人员公知的。近来,开发了具有改善的血清稳定性和循环半衰期的脂质体(美国专利No.5,741,516)。此外,已经描述了将脂质体和脂质体样制剂作为潜在药物载体的多种方法(美国专利No.5,567,434;5,552,157;5,565,213;5,738,868和5,795,587)。
已成功地将脂质体用于许多细胞类型,所述细胞类型通常对通过其他方法的转染具有抵抗力。此外,脂质体不受DNA长度限制(其是基于病毒的递送系统的特征)。已将脂质体有效地用于将基因、药物、放射治疗剂、病毒、转录因子和变构效应物引入多种经培养的细胞系和动物中。此外,已经完成了检查脂质体介导药物递送的有效性的若干次成功的临床试验。
脂质体由分散在水性介质中并自发形成多层同心双层囊泡(也称为多层囊泡(MLV))的磷脂形成。MLV的直径一般为25nm至4μm。MLV的超声处理导致形成直径为200至500.ANG.的在核心中包含水溶液的小单层囊泡(small unilamellar vesicle,SUV)。
或者,可以使用rAAV的纳米胶囊制剂。纳米胶囊通常可以以稳定和可重复的方式捕获物质。为了避免由于细胞内聚合物过载引起的副作用,应使用能够在体内降解的聚合物来设计这样的超微颗粒(尺寸约0.1μm)。预期使用满足这些要求的可生物降解的聚烷基-氰基丙烯酸酯纳米颗粒。
除了上述递送方法之外,还预期将以下技术作为将rAAV组合物递送至宿主的替代方法。在美国专利No.5,656,016中已使用和描述了将超声促渗(sonophoresis)(即,超声)作为用于提高药物渗入并通过循环系统的速率和功效的装置。预期其他药物递送替代方案是骨内注射(美国专利No.5,779,708)、微芯片装置(美国专利No.5,797,898)、眼用制剂(Bourlais等,1998)、透皮基质(美国专利No.5,770,219和5,783,208)和反馈控制递送(美国专利No.5,697,899)。
试剂盒和相关组合物
在一些实施方案中,本文所述的药剂可被组装成药物或诊断或研究试剂盒以促进其在治疗、诊断或研究应用中的使用。试剂盒可以包含容纳有本公开内容的组分的一个或更多个容器和使用说明书。具体地,这样的试剂盒可以包含本文所述的一种或更多种药剂以及描述这些药剂的预期应用和适当用途的说明书。在某些实施方案中,试剂盒中的药剂可以是适用于特定应用和适用于药剂施用方法的药物制剂和剂量。用于研究目的的试剂盒可以包含适当浓度或量的组分以用于进行多种实验。
试剂盒可以被设计成辅助研究人员使用本文所述的方法并且可以采取许多形式。在适用的情况下,试剂盒的每种组合物可以以液体形式(例如,以溶液)或固体形式(例如,干粉末)提供。在某些情况下,一些组合物可以是可组成的或以其他方式可加工的(例如,加工为活性形式),例如通过添加合适的溶剂或其他物质(例如,水或细胞培养基),其可以与或可以不与试剂盒一起提供。如本文使用的“说明书”可以确定说明和/或推广的组分,并且通常包括在本公开内容的包装上或与其有关的书面说明书。说明书还可以包括以任何方式提供的任何口头或电子说明书,以使得使用者将清楚地认识到说明书与该试剂盒有关,例如音像(例如,录像带、DVD等)、因特网和/或基于网络的通信等。书面说明书可以是由管理药品或生物制品制造、使用或销售的政府机构所规定的形式,该说明书还可反映所述机构对用于动物施用的制造、使用或销售的许可。
试剂盒可以包含一个或更多个容器中的本文所述的任一种或更多种组分。作为一个实例,在一个实施方案中,试剂盒可以包含用于混合试剂盒中的一种或更多种组分和/或分离和混合样品并施用于对象的说明书。试剂盒可以包含容纳有本文所述的药剂的容器。所述药剂可以是液体、凝胶或固体(粉末)形式。所述药剂可以无菌制备,包装在注射器中并冷藏运送。或者,其可以被放置在小瓶或其他容器中用于储存。第二容器可以具有无菌制备的其他药剂。或者,试剂盒可以包含预先混合并在注射器、小瓶、管或其他容器中运送的活性剂。试剂盒可以具有将药剂施用于动物所需的一种或更多种或全部组件,例如注射器、局部施用装置或iv针管和包,特别是在用于产生特定体细胞动物模型的试剂盒的情况下。
试剂盒可以具有多种形式,例如泡罩袋、收缩包装袋、真空可密封袋、可密封的热成型盘或类似的袋或盘形式,其中附件松散地包装在袋、一个或更多个管、容器、箱或包中。在增加附件后,可以对试剂盒进行灭菌,从而使容器中的各个附件不会散开。可以使用任何合适的灭菌技术(例如辐射灭菌、热灭菌或本领域已知的其他灭菌方法)将试剂盒灭菌。根据具体应用,试剂盒还可以包含其他组件,例如,容器、细胞培养基、盐、缓冲剂、试剂、注射器、针、用于施用或去除消毒剂的织物如纱布、一次性手套、施用前的药剂支架等。
试剂盒中包含的说明书可以包括用于检测细胞中的潜在AAV的方法。此外,本公开内容的试剂盒可以包含说明书、阴性和/或阳性对照、容器、用于样品的稀释剂和缓冲剂、样品制备管和用于序列比较的参照AAV序列的印刷或电子表。
实施例
实施例1:从黑猩猩组织中分离转录活性新型AAV衣壳序列以用于载体开发
为了寻找倾向于感染灵长类的新型AAV,分析了多个黑猩猩组织中AAV前病毒基因组和cap RNA的存在,其中首先使用一组引物和探针通过qPCR和qRT-PCR来靶向短保守cap序列段。评估了来自两只黑猩猩的六个组织(脑、心脏、肾、肝、肺和脾)的AAV cap序列。数据表明,所有组织均具有可变丰度的AAV,其中肝中的拷贝数最高。随后,进行PCR和RT-PCR克隆来挽救来自黑猩猩DNA和RNA两者的全长衣壳序列。通过测序分析cDNA克隆(例如,VP1的克隆)。通过RT-PCR和PCR分离VP1的总计24个DNA和23个RNA克隆并进行完全测序。有趣的是,这47个克隆中有30个是AAV5样的,其中14个克隆是RT-PCR的产物。
系统进化分析将衣壳克隆分为与AAV3B、AAV4和AAV5密切相关的三个主要组,其可用于基因递送至多种组织(例如,CNS、肾、脾、肝和心脏靶标)。表1列出了所鉴定的AAV衣壳变体。表2提供了与鉴定的变体序列有关的野生型AAV血清型的NCBI登录号。
通过BLAST分析和多重序列比对选择具有与AAV3B、AAV4或AAV5及其自身内部的氨基酸差异的变体cap cDNA克隆,以用于进行进一步表征(表3)。变体衣壳蛋白与野生型AAV血清型之间的氨基酸替换总结在表4-6中。
构建包含示例衣壳(即,CBr-7.4、CBr-7.5和CBr-7.8衣壳)的重组AAV并包装成包含萤光素酶表达载体基因组。对于CBr-7.4、CBr-7.5和CBr-7.8,产生的rAAV的滴度分别为1.3×1010、1.2×1010和1.2×1010个基因组拷贝/ml。用重组AAV转导Huh-7.5肝瘤细胞并检查萤光素酶表达以确认转导和表达(图4)。检查作为对照的AAV9和AAV3B。
表1:新型AAV的序列
表2:AAV CAPSID序列变体
表3:AAV3B变体之间的氨基酸变化
表4:AAV4变体之间的氨基酸变化
表5:AAV5变体之间的氨基酸变化
本公开内容并不将其应用限于本说明书中阐述或附图中所示的构造细节和组件布置。本公开内容能够具有其他实施方案并且能够以多种方式实践或实施。另外,本文使用的措辞和术语是为了描述的目的并且不应被认为是限制。本文使用“包括”、“包含”或“具有”、“含有”、“涉及”及其变体意指涵盖此后列出的项目及其等同物以及另外的项目。
至此已描述了本公开内容的至少一个实施方案的若干方面,应当理解,本领域技术人员将容易想到各种改变、修改和改进。这样的改变、修改和改进旨在成为本公开内容的一部分并且旨在包含在本公开内容的精神和范围内。因此,上述说明书和附图仅作为示例。
Claims (34)
1.重组表达载体,其由选自SEQ ID NO:4至5和10至11的序列组成。
2.分离的腺相关病毒(AAV)衣壳蛋白,其由选自SEQ ID NO:54至55和60至61的序列组成。
3.重组表达载体,其包含编码权利要求2所述的分离的AAV衣壳蛋白之核酸序列。
4.组合物,其包含权利要求2所述的分离的AAV衣壳蛋白。
5.组合物,其包含权利要求2所述的分离的AAV衣壳蛋白和可药用载体。
6.重组AAV(rAAV),其包含权利要求2所述的分离的AAV衣壳蛋白。
7.组合物,其包含权利要求6所述的重组rAAV。
8.权利要求7所述的组合物,其还包含可药用载体。
9.含有核酸序列的宿主细胞,所述核酸序列包含与启动子有效连接的编码序列,其中所述编码序列选自SEQ ID NO:4至5和10至11。
10.组合物,其包含权利要求9所述的宿主细胞和无菌细胞培养基。
11.权利要求10所述的组合物,其还包含冷冻保存剂。
12.权利要求6所述的rAAV在制造用于将至少一种转基因递送至对象的药物中的用途,其中所述rAAV包含至少一种转基因,并且其中所述rAAV感染所述对象靶组织的细胞,其中所述靶组织是脑组织。
13.用于产生体细胞转基因动物模型的方法,其包括向非人动物施用权利要求6的rAAV,其中所述rAAV包含至少一种转基因,并且其中所述rAAV感染所述非人动物靶组织的细胞,其中所述靶组织是脑组织。
14.权利要求12所述的用途,其中所述至少一种转基因是蛋白质编码基因。
15.权利要求12所述的用途,其中所述至少一种转基因编码小干扰核酸。
16.权利要求15所述的用途,其中所述小干扰核酸是miRNA。
17.权利要求15所述的用途,其中所述小干扰核酸是抑制所述对象或动物中至少一种miRNA之活性的miRNA海绵或TuD RNA。
18.权利要求17所述的用途,其中所述miRNA在所述靶组织的细胞中表达。
19.权利要求13所述的方法,其中所述转基因表达包含至少一个miRNA结合位点的转录物,其中所述miRNA通过与所述结合位点杂交来抑制所述靶组织以外的组织中所述转基因的活性。
20.权利要求13所述的方法,其中所述转基因包含组织特异性启动子或诱导型启动子。
21.权利要求20所述的方法,其中所述组织特异性启动子是肝特异性甲状腺素结合球蛋白启动子、胰岛素启动子、胰高血糖素启动子、生长抑素启动子、胰多肽启动子、突触蛋白-1启动子、肌酸激酶启动子、哺乳动物结蛋白启动子、α-肌球蛋白重链启动子或心肌肌钙蛋白T启动子。
22.权利要求12所述的用途,其中经静脉内、透皮、眼内、鞘内、经口、肌内、皮下、鼻内或通过吸入来施用所述rAAV。
23.权利要求12所述的用途,其中所述对象选自小鼠、大鼠、兔、狗、猫、绵羊、猪和非人灵长类。
24.权利要求12所述的用途,其中所述对象是人。
25.用于产生rAAV的试剂盒,所述试剂盒包含:
容纳有由选自SEQ ID NO:4至5和10至11的序列组成之分离核酸序列的容器。
26.权利要求25所述的试剂盒,其还包含用于产生所述rAAV的说明书。
27.重组AAV(rAAV)载体,其中所述rAAV载体包含转基因,并且其中使用权利要求25所述的试剂盒产生所述rAAV。
28.试剂盒,其包含:
容纳有具有权利要求2所述的分离AAV衣壳蛋白的重组AAV的容器。
29.权利要求28所述的试剂盒,其中所述容器是注射器。
30.分离的AAV衣壳蛋白,其由选自SEQ ID NO:4至5和10至11的核酸序列编码。
31.权利要求30所述的分离的AAV衣壳蛋白,其中所述衣壳蛋白是VP1衣壳蛋白。
32.权利要求30所述的分离的AAV衣壳蛋白,其中所述衣壳蛋白是VP2衣壳蛋白。
33.权利要求30所述的分离的衣壳蛋白,其中所述衣壳蛋白是VP3衣壳蛋白。
34.包含权利要求30至33中任一项所述的衣壳蛋白的假型AAV。
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RU2738421C2 (ru) | 2020-12-14 |
JP7023108B2 (ja) | 2022-02-21 |
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CN107073051A (zh) | 2017-08-18 |
AU2021206885A1 (en) | 2021-08-12 |
AU2015335923A1 (en) | 2017-04-20 |
EP3209311A4 (en) | 2018-08-08 |
JP2017532966A (ja) | 2017-11-09 |
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